Vertebral Fracture Risk Reduction Research Articles

SAT339 Osteopenia In The Setting of Mild Autonomous Cortisol Secretion

Abstract Disclosure: J.J. Mao: None. K.C. McCowen: None. C. Choe: None. Jimmy J. Mao, MD (1); Karen C. McCowen (1); Charles H. Choe (1)(1) Division of Endocrinology, Diabetes, and Metabolism, University of California San Diego, La Jolla, CA. Background: Over 80% of adrenal incidentalomas are benign adrenal cortical adenomas, of which 30-50% are found to have mild autonomous cortisol secretion (MACS). Bone fragility is a known complication of MACS. Clinical Case: A 57-year-old postmenopausal female with no prior history of fracture, venous thromboembolism, and atherosclerotic cardiovascular disease, was referred for incidental bilateral adrenal nodules. Body mass index was normal at 21 kg/m2, and no clinical stigmata of Cushing syndrome were noted on physical exam. Unenhanced computed tomography scan revealed a 4.6 cm right adrenal nodule and a 3.3 cm left adrenal nodule; both nodules measured less than -18 Hounsfield Units. Biochemical work-up for pheochromocytoma, primary aldosteronism, and non-classical congenital adrenal hyperplasia was negative. Evaluation for hypercortisolism revealed a morning cortisol of 20.3 mcg/dL (ref. 4-22 mcg/dL) with concurrent adrenocorticotropic hormone of <5 pg/mL (ref. 6-50 pg/mL), 24-hour urine free cortisol of 16.9 mcg (ref. 4-50 mcg), and midnight salivary cortisol of 0.07 mcg/dL (ref. <0.09 mcg/dL). A 1 mg dexamethasone suppression test measured on two separate occasions was elevated at 6.3 mcg/dL and 7.9 mcg/dL (ref. <1.8 mcg/dL). A subsequent 8 mg dexamethasone suppression test was also elevated at 6.1 mcg/dL (ref. <1.8 mcg/dL). The diagnosis of MACS was made. A bone mineral density (BMD) scan revealed T-scores at the right femoral neck, left femoral neck, and lumbar spine at -1.6, -1.3, and -0.8, respectively. Ten-year probability of major osteoporotic fracture and hip fracture were 8.3% and 1.0%, respectively. To reduce the risk for future fractures, the decision was made to proceed with adrenal vein sampling (AVS) in preparation for potential adrenalectomy. Conclusion: MACS is the most frequent hormonal abnormality in adrenal incidentalomas, with an estimated prevalence of 0.8-2 cases per 1000 persons. A previous prospective study found that surgical cure of unilateral MACS may lead to a substantial risk reduction (up to 15-fold) of future incident asymptomatic vertebral fractures. Additionally, the highest risk for clinical fracture in those with adrenal adenomas (either nonfunctional or with cortisol hypersecretion) appears to occur at 7-10 years after initial diagnosis. BMD does not perfectly correlate with fracture risk, so unilateral adrenalectomy (if lateralization is observed on AVS) and/or pharmacotherapy should be strongly considered in patients with an expected longevity of >10 years even with mild osteopenia and low fracture risk assessment tool scores. Presentation: Saturday, June 17, 2023

P02 When should we stop the antiresorptive medications in patients with osteoporosis?

Abstract Introduction Bisphosphonates are first line and denosumab is the latest antiresorptive agent approved for osteoporosis treatment. Those drugs showed a reduction in vertebral fracture risk and other non-vertebral by 35-70%. One of the rare adverse events with antiresorptive treatment is medicine-related osteonecrosis of jaw (MONJ) which mainly occur in individuals receiving high doses for the treatment of cancer. Recent research found true incidence of MONJ is very low despite public perception. Studies indicate that 50% of women and 20% of men aged over 50 years will experience an osteoporosis-related fracture which have significant associated morbidity and mortality. Case description We report a case of an osteoporosis patient who was treated with alendronate followed by denosumab and presented with suspicion of MONJ. In 2014, a 77-year-old female was referred following right neck of fragility femur fracture. DXA showed osteoporosis (T- score of the spine −3.2, T- score total hip −2.4 and T- score of left neck of femur −2.1). She was initially treated with four years of alendronate (70 mg once weekly) but sustained a pubic rami fracture. Hence, she was then treated with six monthly injections of denosumab (60 mg subcutaneously). After three injections, she developed jaw pain. She was reviewed by her dentist who advised her to stop the denosumab for suspected MONJ. She was then seen by the oral surgeon who confirmed that there was a piece of bone in UR6 socket but with no bone sequestrum and this piece of bone was removed under local anaesthesia with good healing. She was advised to restart denosumab. The patient was extremely worried and anxious about denosumab recommencement and teriparatide was considered. After completion of teriparatide treatment her DXA still showed osteoporosis (T- score of the spine −2.1, T- score of total hip −2.2 and T- score of left neck of femur −2.6) with stable changes in the hip and improvement in the spine. On review, she continued to have concerns about antiresorptive treatment. Further oral surgeon review stated low grade infection around UL7 with poor gum condition around UR6 and LR6 with some bleeding points but no definite diagnosis of MRONJ. It was advised that any further manoeuvre involving tooth extraction will be conducted by the oral surgeon. Following this, the patient was happy to consider zoledronic acid infusions. She is due for her 3rd zoledronate infusion and is undergoing regular dental checks. Discussion The incidence of MONJ in patients taking oral bisphosphonates for osteoporosis is relatively low, estimated to be less than 1% (0.001% to 0.01%). However, the risk is higher for individuals receiving higher doses of intravenous bisphosphonates for the treatment of cancer or bone-related complications of cancer. The incidence of MONJ in cancer patients receiving intravenous bisphosphonates ranges from 1% to 15%. More clinical studies have been published that describe the relation between MONJ and denosumab in cancer patients with the risk of MONJ varying between 0.7 to 1.9% (70 to 90 cases per 10,000 patients). However, in patients with osteoporosis treated with denosumab, the incidence of MONJ is lower, resulting in an even lower frequency of 0.04% (4 cases per 10,000 patients). It is understandable that there is a significant concern amongst dentists about MONJ risk with antiresorptive treatment, but it is paramount that the patients are made aware of the fracture risk and its significant effect on quality of life. Many patients are not aware that more than 20% of patients die in the first year after a hip fracture from complications surrounding the fracture and a significant number of patients lose their long-term ability to live independently. Vertebral fractures have significant morbidity and the mortality rate of 72% at 5 years and 90% at 7 years. Key learning points Most dentists are often reluctant to treat patients on anti-resorptive medications due to the risk of MONJ which results in patient’s concerns about treatment and subsequent stoppage of osteoporosis treatment leading to fracture risks. Thus, it is imperative to assure the patients of benefits of the anti-resorptive medications versus the MONJ risks. This calls for increased awareness and national guidelines for the prevention and management of ONJ in osteoporosis patients treated with antiresorptive.

Denosumab improves trabecular bone score in relationship with decrease in fracture risk of women exposed to aromatase inhibitors.

Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs. 241 consecutive women (median age 58years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18-24months of follow-up. During the study period, 139 women (57.7%) received denosumab 60mg every 6months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs. Denosumab significantly increased TBS values (from 1.270 to 1.323; P < 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282; P = 0.021). During treatment with BPs, TBS did not significantly change (P = 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (P = 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (P = 0.003), without significant differences in changes of BMD at any skeletal site. TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.

Effect of denosumab treatment on bone mineral density and bone turnover markers in osteoporotic patients: real-life experience 2-year follow-up.

The long-term efficacy of anti-osteoclastic drugs in treatment of osteoporosis is well known. Denosumab, a novel human monoclonal antibody, is an anti-osteoclastic agent that has been shown to lead to reductions in vertebral, nonvertebral, and hip fracture risk in randomized and observational studies. Real-life data of this agent is increasing. In this study, we presented our real-life data about the 2-year follow-up of patients under denosumab treatment. Osteoporotic patients who were treated with at least one denosumab injection between 2014 and 2020years were included. Clinical and demographic data, bone turnover markers, and radiological reports (bone mineral densitometry (BMD), vertebral x-ray) were obtained from patient files retrospectively. A total of 305 patients (f/m: 275/30, 68.1 ± 11.05years) were included. The median injection number was 4 (1-10). Two hundred seventy-three patients (89.8%) were persistent on treatment at the 12th month; 175 patients (57.3%) were persistent at 24th month. Sixty-eight patients (22%) were not using denosumab anymore, 55 of the patients were not continuing by doctor desicion and 13 were not continuing due to patient-related causes. Median BMD levels significantly increased from 0.809 (0.2-1.601, IQR: 0.136) to 0.861 (0.517-1.607, IQR: 0.14) in L1-L4 and from 0.702 (0.349-0.997, IQR: 0.125) to 0.745 (0.508-1.008, IQR: 0.137) in femur area at the 24th month of treatment. An improvement of 8.04% in L1-L4 BMD and 4.5% in femur neck BMD levels at the 24th month of treatment was observed. There was a significant decrease in bone turnover markers at the 24th month of treatment. In our group of patients under denosumab treatment, 53% of persistence was found at 24months and associated with improvement in BMD levels without any significant side effects except one case with urticarial reaction. Denosumab leads to improvements in BMD levels and is a well-tolerated agent in a real-life setting comparable to results of randomized controlled studies in patients with different comorbidities.

Hypercalcemia in a Patient Treated With Abaloparatide

Abstract Introduction: The antifracture efficacy of newer agents like PTHrP analogues is promising but knowledge about the mechanism of action and safety profile is needed in order to use these agents effectively. The reported incidence of hypercalcemia defined as albumin-adjusted serum calcium ≥10.7mg/dL was 3.4% in Abaloparitide. Case Presentation: A 59 year-old female with past medical history significant for diabetes mellitus type 2, hypothyroidism, necrotizing autoimmune myositis, osteoporosis and renal stones presented with complaints of generalized body aches and pains with swelling and redness of the left leg. The patient was diagnosed with osteoporosis based on atraumatic L4 compressive injury involving superior end plate. Her only DXA scan was 8 years ago which showed osteopenia, with the lowest T score of -1.2 at lumbar spine. Subsequent evaluation with DXA scan was unable to be performed due to physical disabilities. She was intolerant to oral bisphosphonates and was started on abaloparatide subcutaneous injections 2 weeks prior to her current admission. Her physical examination was positive for obesity, proximal muscle weakness and bilateral leg edema with bruises and left leg erythema. Laboratory findings showed hypercalcemia with corrected calcium levels of 12.48 mg/dl, suppressed intact PTH 4 pg/ml. Evaluations for secondary causes of hypercalcemia were negative. Her last dose of abaloparatide injection was the morning prior to her presentation to the emergency room. The patient was treated with IV fluids and her calcium level improved within 24 hours with normalization of intact PTH level in 72hrs. Abaloparatide injection was suspended on admission. Hypercalcemia with suppressed PTH was most likely secondary to abaloparatide given the timing of the hypercalcemia after the injection and resolution of hypercalcemia and normalization of PTH. Conclusions: Abaloparatide is a peptide that selectively binds to the RG conformation of the parathyroid hormone type 1 receptor. Abaloparatide is increasingly used following the results from the ACTIVE and ACTIVExtend trials which demonstrate significant increase in bone mineral density and risk reduction of vertebral, nonvertebral, clinical, and major osteoporotic fractures. Hypercalcemia was reported as a side effect, but there is no guidance on further evaluation or management of these patients. The incidence of hypercalcemia defined as albumin-adjusted serum calcium ≥10.7mg/dL is 3.4 % and risk is increased in patients with renal impairment. As in our case, transient hypercalcemia and PTH suppression may be associated with abaloparatide. Efficacy of abaloparatide and impact on bone density with delay or interrupted treatment are not available. Further studies are needed to guide monitoring and treatment of clinically symptomatic transient hypercalcemia in patients taking abaloparatide.

Retraction Note to: Anti-Fracture Efficacy of Risedronic Acid in Men : A Meta-Analysis of Randomized Controlled Trials.

Background and objective: Male osteoporosis is an important public health issue and remains undertreated. We performed this meta-analysis to clarify the anti-fracture efficacy of risedronic acid in men. Methods: Randomized controlled trials (RCTs) in men receiving risedronic acid or placebo published between 1980 and September 2008 were searched for in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Studies with a follow-up of at least 12 months and providing the incidence of fractures were considered for inclusion in the review. Two independent reviewers assessed the methodological quality of the included studies and performed data extraction. Analysis of pooled data was carried out using Revman 4.2 software. Results: Four RCTs met the inclusion criteria and permitted a pooled estimate of effectiveness. Relative risk with 95% confidence intervals for pooled effect under fixed effects model were: 0.31 (0.16, 0.60) for vertebral fractures and 0.40 (0.23, 0.70) for nonvertebral fractures, suggesting a 69% risk reduction of vertebral fractures and a 60% risk reduction of nonvertebral fracture with risedronic acid treatment in men. Conclusion: The results of this meta-analysis show that risedronic acid treatment is associated with a reduced risk of fractures in men.

Differential Risk of Incident Fractures Depending on Intensity and Frequency of Physical Activity According to Cognitive Status: A Nationwide Longitudinal Study.

Background: Previous studies have demonstrated an increased risk of fractures in subjects with various degrees of cognitive impairments. Recently, there has been growing recognition of the vital effect of physical activity (PA) on delay and prevention of fractures in older adults.Objectives: This study aimed to evaluate the optimal intensity and frequency of PA needed to prevent fractures in cognitively preserved older adults (CP), participants with subjective cognitive decline (SCD), and dementia patients using a large-scale nationwide cohort study.Methods: Data from a nationwide health screening program for individuals at the transitional age of 66 years were used in this study. A total of 968,240 subjects was enrolled, followed from 2007 to 2014, and classified as CP (n = 759,874), SCD (n = 195,365), or dementia group (n = 13,001). Adjusted hazard ratios (aHRs) by demographic and known risk factors for fractures were evaluated to identify the impact of various frequency and intensity PA on the occurrence of hip, vertebral, and limb fractures.Results: In CP participants, the most noticeable reduction of hip and vertebral fracture risk was shown in those performing vigorous-intensity PA at least three times per week. In the SCD group, the risk decrement in hip and vertebral fractures was most prominent in subjects who performed multiple-intensity PAs at least three times a week regardless of intensity. In the dementia group, only high-frequency walking and high-frequency & multiple-intensity PA decreased the risk of hip fractures compared with absence of PA.Conclusion: These findings suggest a role for various PA intensity and frequency levels to prevent hip and vertebral fractures according to cognitive status. Further study is needed to validate the effects of PA intensity and frequency proposed in this study on fractures according to cognitive status.

The Interaction of Acute-Phase Reaction and Efficacy for Osteoporosis After Zoledronic Acid: HORIZON Pivotal Fracture Trial.

Zoledronic acid (ZOL) as a yearly infusion is effective in reducing fracture risk. An acute-phase reaction (APR), consisting of flu-like symptoms within 3 days after infusion, is commonly seen. The objective of this analysis was to investigate whether APR occurrence influences drug efficacy. This analysis uses data from the 3-year randomized clinical trial, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APRs were identified as adverse events within 3 days of first infusion with higher frequency in ZOL than placebo. To compare mean 3-year change in bone mineral density (BMD) in ZOL versus placebo, among women with and without APR, t tests were used. Logistic regression was used to examine the relationship between APR occurrence and odds of incident morphometric vertebral fracture. Cox regression was used to determine the risk of nonvertebral and hip fractures for women with versus without APR. Logistic and Cox models were used to determine the risk of incident fracture in ZOL versus placebo for women with and without an APR. The analysis included 3862 women in the ZOL group and 3852 in placebo, with 42.4% in ZOL versus 11.8% in placebo experiencing an APR. The difference in BMD mean change for ZOL versus placebo was similar for women with and without an APR (all p interaction >0.10). Among ZOL women, those with APR had 51% lower vertebral fracture risk than those without (odds ratio [OR]=0.49, p< 0.001). A similar but nonsignificant trend was observed for nonvertebral and hip fracture (relative hazard [RH]=0.82, p =0.10; RH=0.70, p =0.22, respectively). There was a greater treatment-related reduction in vertebral fracture risk among women with APR (OR=0.19) than those without (OR=0.38) (p interaction=0.01). Our results suggest that women starting ZOL who experience an APR will have a larger reduction in vertebral fracture risk with ZOL. © 2021 American Society for Bone and Mineral Research (ASBMR).

The challenge of long-term adherence: The role of bone turnover markers in monitoring bisphosphonate treatment of osteoporosis.

Oral Bisphosphonates (BPs) are the mainstay of osteoporotic treatment, however long-term adherence remains a challenge, primarily owing to the chronic character of the disease and the regimen complexity. Poor compliance has been shown to have a clear link to fracture risk. The role of bone turnover markers (BTMs) as a tool to ascertain adherence and response to therapy is supported by their rapid response to treatment; a decrease in values is witnessed within days or weeks of commencing treatment. A greater reduction of serum CTX and NTX is evidenced with alendronate and ibandronate compared to risedronate. A change in bone formation BTMs appears to be related to vertebral fracture risk reduction, whereas no significant relationship is evident for hip and non-vertebral fractures. The utility of BTMs as an adjunct for monitoring withdrawal of treatment with oral BP has also been suggested. Finally, studies evaluating BTMs as an intervention, failed to demonstrate any effect on adherence. This review explores the challenge of long-term adherence with bisphosphonates and provides an analytic framework with respect to the role of BTMs in monitoring bisphosphonate treatment, adherence and the offset of treatment effect.

Medications associated with fracture risk in patients with rheumatoid arthritis

ObjectiveTo examine the fracture risk with use of disease-modifying antirheumatic drugs (DMARDs), statins, proton pump inhibitors (PPIs), opioids, non-opioid analgesics and psychotropic medications in a US-wide observational rheumatoid arthritis (RA)...

Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis

SummaryThis network meta-analysis assessed the efficacy of abaloparatide versus other treatment options to reduce the risk of fractures in women with postmenopausal osteoporosis. The analysis indicates that abaloparatide reduces the risk of fractures in women with postmenopausal osteoporosis versus placebo and compared with other treatment options.IntroductionThis network meta-analysis (NMA) assessed the relative efficacy of abaloparatide versus other treatments to reduce the risk of fractures in women with postmenopausal osteoporosis (PMO).MethodsPubMed®, Embase®, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published before December 20, 2017, that included women with PMO who were eligible to receive interventions for primary or secondary fracture prevention. The NMA was conducted by fracture site (vertebral [VF], nonvertebral [NVF], and wrist), with the relative risk (RR) of fracture versus placebo the main clinical endpoint. The NMA used fixed-effects and random-effects approaches.ResultsA total of 4978 articles were screened, of which 22 were included in the analysis. Compared with other treatments, abaloparatide demonstrated the greatest treatment effect relative to placebo in the VF network (RR = 0.13; 95% credible interval [CrI] 0.04–0.34), the NVF network (RR = 0.50; 95% CrI 0.28–0.85), and the wrist fracture network (RR = 0.39; CrI 0.15–0.90). Treatment ranking showed that abaloparatide had the highest estimated probability of preventing fractures in each of the networks (79% for VF, 70% for NVF, and 53% for wrist fracture) compared with other treatments. Individual networks demonstrated a good level of agreement with direct trial evidence and direct pair-wise comparisons.ConclusionsThis NMA indicates that abaloparatide reduces the RR of VF, NVF, and wrist fracture in women with PMO with or without prior fracture versus placebo, compared with other treatment options. Limitations include that adverse events and drug costs were not considered, and that generalizability is limited to the trial populations and endpoints included in the NMA.

Function of low back muscle exercise : Preventive effect of refracture analysis of postoperative vertebral fractures.

Low back muscles exercise reportedly influence the risk of osteoporotic vertebral fractures. The exact relationship between the low back muscles exercise and the incidence of vertebral refractures remain unclear. To investigate the ability of exercise to strengthen the low back muscles to prevent vertebral refracture after surgery, through clinical analysis of the vertebral fracture risk reduction program. In total 152 patients with vertebral fractures who had undergone percutaneous vertebroplasty (PVP) and anti-osteoporosis treatment were randomly divided into observation and control groups. The observation group performed exercises to strengthen the back muscles after surgery. The clinical efficacy and incidence of re-fractures were compared between groups. The observation group had reduced physical dysfunction and pain following surgery. After 3months, the vertebral body height had significantly decreased (P < 0.05) in the control group but not in the observation group (P > 0.05). In the observation and control groups, the incidence of vertebral refractures was 9.2% (7/76) and 17.1% (13/76), respectively (P < 0.05). Postoperative exercise to strengthen the back muscles can improve physical function, relieve pain and promote the recovery of vertebral height; it can also assist in maintaining bone density, thereby significantly reducing the risk of refracture. This approach is safe and effective and can help improve the quality of life in patients with vertebral fractures.

Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice.

Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites.

Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review.

Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with bone fragility and increased fracture risk. However, little is known regarding the effect of anti-osteoporotic treatment on bone mineral density (BMD) and/or fracture risk in these patients. We aimed to systematically investigate the efficacy of anti-osteoporotic medications in patients with diabetes in comparison with non-diabetic subjects. MEDLINE and Scopus databases were searched (up to 31st October 2017). Nine studies fulfilled the pre-defined inclusion criteria [patients with T2DM (n = 8) or either T1DM or T2DM (n = 1)]. Regarding fracture risk, five studies were identified. Alendronate demonstrated comparable vertebral anti-fracture efficacy in patients with and without diabetes (n = 2), whereas non-vertebral fracture risk was either the same (n = 1) or higher in diabetic patients (n = 1). Raloxifene also demonstrated comparable vertebral anti-fracture efficacy in both groups (n = 2), without any effect on non-vertebral fractures in either group. In one study, diabetic patients exposed to raloxifene demonstrated the same vertebral and non-vertebral fracture risk with non-diabetic patients. Teriparatide (n = 1) demonstrated the same non-vertebral fracture rates in both patients with and without T2DM. Regarding BMD, equal increases in spine BMD were observed with alendronate (n = 4), risedronate (n = 1), and teriparatide (n = 1). With respect to hip BMD, similar increases were observed with teriparatide (n = 1), whereas data regarding alendronate were controversial (n = 3). No eligible study was found for zoledronic acid, ibandronate, strontium ranelate, denosumab, or bazedoxifene. The presence of diabetes does not alter anti-osteoporotic treatment response, regarding BMD increase and vertebral fracture risk reduction.

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression.

Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2 = 0.82 [p < 0.001] and r2 = 0.75 [p = 0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2 = 0.33 [p = 0.053] and r2 = 0.53 [p = 0.065], respectively) and hip fracture (r2 = 0.17 [p = 0.24] and r2 = 0.43 [p = 0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2017 American Society for Bone and Mineral Research.

Targeting Sclerostin in Postmenopausal Osteoporosis: Focus on Romosozumab and Blosozumab.

Most current treatments for osteoporosis inhibit bone resorption and reduce total fracture numbers by about one-quarter. The identification of the osteocytic protein sclerostin as a potent regulator of bone turnover and bone density has led to the development of a new therapeutic class-agents that inhibit sclerostin activity, resulting in increased bone formation and reduced bone resorption. Romosozumab and blosozumab are monoclonal antibodies that bind to sclerostin, reducing its inhibition of Wnt signaling. They have comparable activities in phase I and II studies, doubling formation markers, halving resorption indices, and increasing spine bone density by >10% over 12months. Only romosozumab has progressed to phase III, where the first study showed a 73% reduction in vertebral fracture risk and a 36% reduction in clinical fractures at 1year. It was well-tolerated. A further phase III study will conclude in 2017. Romosozumab is a very promising medication in the management of established osteoporosis, but much remains to be done to determine its optimal duration and sequence of administration.

Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research.

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.

Efficacy of bisphosphonates against osteoporosis in adult men: a meta-analysis of randomized controlled trials.

This meta-analysis of published randomized controlled trials (RCTs) aimed to analyze the efficacy of administration of bisphosphonates in men with osteoporosis. Compared with placebo, bisphosphonates could reduce the risk of vertebral and non-vertebral fractures, reduce bone-specific alkaline phosphatase (BSAP) and C-terminal telopeptide of type I collagen (CTX), and increase bone mineral density (BMD). Bisphosphonates are well-investigated antiresorptive medications, approved as first-line drugs for osteoporosis in postmenopausal women. However, there is a paucity of high-quality evidence regarding the efficacy of bisphosphonates administered for osteoporosis in adult men. The aim of this meta-analysis was to analyse the efficacy of administration of bisphosphonates in men based on published RCTs. PubMed, Embase, MEDLINE, and the Cochrane library were searched, and mean differences were calculated to evaluate the efficacy of bisphosphonates on reducing the risk of vertebral and non-vertebral fracture, reducing bone-turnover biomarkers, and increasing BMD. Nine RCTs were included and the total number of participants was 2464. Compared with placebo, the efficacy of bisphosphonates on vertebral and non-vertebral fracture risk reduction was confirmed [for vertebral fracture, RR (95% CI) 0.36 (0.24, 0.56), P < 0.01; for non-vertebral fracture, RR (95% CI) 0.52 (0.32, 0.84), P < 0.01)] and heterogeneity was insignificant. The efficacy of bisphosphonates on reducing BSAP [MD (95% CI) -24.41 (-26.19, -22.62), P < 0.01) and CTX [MD (95% CI) -34.51 (-41.03, -27.98), P < 0.01)] was significant. A sensitivity analysis was applied to explain the origination of heterogeneity in analysis of decreasing of BSAP. BMD was increased in the bisphosphonates group compared with the control group at lumbar spine, femoral neck, and total hip (P < 0.01), and the heterogeneity of all comparisons was significant. Compared with placebo, bisphosphonates could decrease the risk of vertebral and non-vertebral fractures, reduce BSAP and CTX, and increase BMD in men with osteoporosis.

Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral fractures in postmenopausal osteoporotic women

Objective:Compare the efficacy of bazedoxifene with oral bisphosphonates for reduction of vertebral fracture risk in postmenopausal osteoporotic (PMO) women and in higher-risk patients based on evidence from randomized controlled trials (RCTs).Methods:Eight RCTs assessing vertebral fracture risk reduction with oral bisphosphonates (n = 7) or bazedoxifene (n = 1) were identified by a systematic literature review. Individual study results were pooled in a network meta-analysis (NMA) to indirectly compare treatment effects for overall PMO women and a higher-risk subgroup (FRAX ≥ 20%). Three sets of NMA analyses were conducted: aggregate data (AD) from the bisphosphonate RCTs and bazedoxifene RCT for the full population or the FRAX ≥20% subgroup (NMA AD); bisphosphonate AD and bazedoxifene AD from each FRAX subgroup adjusted for baseline risk (NMA AD meta-regression); and bisphosphonate AD and bazedoxifene individual patient data (IPD) adjusted for baseline risk/FRAX (NMA AD/IPD meta-regression).Results:For the overall population, bisphosphonates had lower fracture risks versus bazedoxifene although there is considerable uncertainty in supporting one intervention over another. The relative risk reduction (RRR) for bazedoxifene was −0.23 (95% CrI: −1.11, 0.27) versus ibandronate, −0.17 (−0.76, 0.22) versus alendronate, and −0.06 (−0.62, 0.30) versus risedronate. Results from the meta-regression analyses were similar. For the FRAX ≥20% population, estimated fracture rates with bazedoxifene were lower than with bisphosphonates, but again the uncertainty limits strong interpretation. The RRR for bazedoxifene was 0.51 (−0.31, 0.83) versus ibandronate, 0.53 (−0.18, 0.83) versus alendronate, and 0.57 (−0.07, 0.85) versus risedronate. The meta-regression analyses showed comparable findings.Conclusion:The analyses only considered vertebral fractures for oral bisphosphonates versus bazedoxifene, and IPD was available only for bazedoxifene. In light of this, bazedoxifene is comparable to bisphosphonates in the overall PMO population and at least as effective as bisphosphonates for preventing vertebral fractures among higher-risk PMO patients. The findings suggest bazedoxifene performs better in higher-risk PMO than in the overall PMO.

Changes in bone mineral density, bone turnover markers, and vertebral fracture risk reduction with once weekly teriparatide

Objective:We aimed to evaluate the surrogacy of bone mineral density and bone turnover markers for incident vertebral fracture using data from 237 patients treated with once weekly 56.5 μg teriparatide or placebo.Methods:This analysis was conducted using data from the Teriparatide Once-Weekly Efficacy Research trial, a randomized, double-blind, placebo-controlled trial for patients with severe osteoporosis in Japan. A total of 237 subjects (placebo group, n = 130; teriparatide group, n = 107) were assessed at baseline and at 72 weeks. Main outcome measures included estimation of the treatment effects of once weekly teriparatide on vertebral fracture risk reduction using percentage changes in lumbar bone mineral density and bone turnover markers.Results:The percentage change in lumbar bone mineral density was 6.69% in the teriparatide group compared with 0.28% in the placebo group (p < 0.01). One incident vertebral fracture occurred in the teriparatide group compared with 16 in the placebo group. The unadjusted and adjusted hazard ratios of the teriparatide group compared with the placebo group were 0.07 (95% confidence interval: 0.01 to 0.56) and 0.64 (95% confidence interval: 0.06 to 6.36), respectively. The proportion of treatment effect explained by changes in lumbar bone mineral density was 83% (Freedman’s method) and 66% (Chen’s method). There were no notable changes in hazard ratios if we adjusted for bone turnover markers.Conclusions:Most of the vertebral fracture risk reduction with once weekly 56.5 μg teriparatide is explained by changes in lumbar bone mineral density rather than changes in bone turnover markers.