Potent Antiresorptive Agents Research Articles

Standard Versus Cyclic Teriparatide and Denosumab Treatment for Osteoporosis: A Randomized Trial.

In the absence of an intervening antiresorptive agent, cyclic administration of teriparatide does not increase bone mineral density (BMD) more than standard daily therapy. Because denosumab is a potent antiresorptive agent with a rapid off-effect, we hypothesized that it might be the optimal agent to help maximize bone gains with cyclic teriparatide. In this 3-year protocol, 70 postmenopausal women with osteoporosis were randomized to 18 months of teriparatide followed by 18 months of denosumab (standard) or three separate 12-month cycles of 6 months of teriparatide followed by 6 months of denosumab (cyclic). BMD (dual-energy X-ray absorptiometry [DXA]) measurements of lumbar spine (LS), total hip (TH), femoral neck (FN), and 1/3 radius (RAD) were performed every 6 months and total body bone mineral (TBBM) at 18 and 36 months. Baseline descriptive characteristics did not differ between groups except for a minimal difference in LS BMD but not T-score (mean age 65 years, mean LS T-score - 2.7). In the standard group, BMD increments at 36 months were: LS 16%, TH 4%, FN 3%, and TBBM 4.8% (all p < 0.001 versus baseline). In the cyclic group, 36-month BMD increments were similar: LS 12%, TH 4%, FN 4%, and TBBM 4.1% (all p < 0.001 versus baseline). At 36 months, the LS BMD increase with standard was slightly larger than with cyclic (p = 0.04), but at 18 months, in the cyclic group, there was no decline in RAD or TBBM (p = 0.007 and < 0.001, respectively, versus standard). Although the cyclic regimen did not improve BMD compared with standard at 36 months, there appeared to be a benefit at 18 months, especially in the highly cortical skeletal sites. This could be clinically relevant in patients at high imminent risk of fracture, particularly at nonvertebral sites. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Reduced Bone Loss Is Associated With Reduced Mortality Risk in Subjects Exposed to Nitrogen Bisphosphonates: A Mediation Analysis.

Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. © 2019 American Society for Bone and Mineral Research.

Effects of denosumab on bone metabolism and bone mineral density in kidney transplant patients: a systematic review and meta-analysis

The use of immunosuppressive agents, especially glucocorticoids, are associated with increased risks of bone loss in kidney transplant patients. Denosumab, a potent antiresorptive agent, has been shown to increase bone mineral density (BMD) in patients with CKD. However, its effects on bone metabolism and BMD in kidney transplant patients remain unclear. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through April 2018 to identify studies evaluating denosumab's effect on changes in bone metabolism and BMD from baseline to post-treatment course in kidney transplant patients. Study results were pooled and analyzed utilizing random-effects model. The protocol for this systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42018095055). Five studies (a clinical trial and four cohort studies) with a total of 162 kidney transplant patients were identified. The majority of patients had a baseline eGFR ≥ 30mL/min/1.73m2. After treatment (≥ 6 to 12months), there were significant increases in BMD with standardized mean differences (SMDs) of 3.26 (95% CI 0.88-5.64) and 1.83 (95% CI 0.43 to 3.22) for lumbar spine and femoral neck, respectively. There were also significant increases in T scores with SMDs of 0.92 (95% CI 0.58 to 1.25) and 1.14 (95% CI 0.17 to 2.10) for lumbar spine and femoral neck, respectively. After treatment, there were no significant changes in serum calcium (Ca) or parathyroid hormone (PTH) from baseline to post-treatment course (≥ 6months) with mean differences (MDs) of 0.52 (95% CI, - 0.13 to 1.16) mmol/L and - 13.24 (95% CI, - 43.85 to 17.37) ng/L, respectively. The clinical trial data demonstrated more asymptomatic hypocalcemia in the denosumab (12 episodes in 39 patients) than in the control (1 episode in 42 patients) group. From the cohort studies, the pooled incidence of hypocalcemia following denosumab treatment was 1.7% (95% CI 0.4 to 6.6%). All reported hypocalcemic episodes were mild and asymptomatic, but the majority of patients required Ca and vitamin D supplements. Among kidney transplant patients with good allograft function, denosumab effectively increases BMD and T scores in the lumbar spine and femur neck. From baseline to post-treatment, there are no differences in serum Ca and PTH. However, mild hypocalcemia can occur following denosumab treatment, requiring monitoring and titration of Ca and vitamin D supplements.

The enigma of atypical femoral fractures: A summary of current knowledge.

Atypical femoral fractures (AFF) are stress or ‘insufficiency’ fractures, often complicated by the use of bisphosphonates or other bone turnover inhibitors. While these drugs are beneficial for the intact osteoporotic bone, they probably prevent a stress fracture from healing which thus progresses to a complete fracture.Key features of atypical femoral fractures, essential for the diagnosis, are: location in the subtrochanteric region and diaphysis; lack of trauma history and comminution; and a transverse or short oblique configuration.The relative risk of patients developing an atypical femoral fracture when taking bisphosphonates is high; however, the absolute risk of these fractures in patients on bisphosphonates is low, ranging from 3.2 to 50 cases per 100,000 person-years.Treatment strategy in patients with AFF involves: radiograph of the contralateral side (computed tomography and magnetic resonance imaging should also be considered); dietary calcium and vitamin D supplementation should be prescribed following assessment; bisphosphonates or other potent antiresorptive agents should be discontinued; prophylactic surgical treatment of incomplete AFF with cephalomedullary nail, unless pain free; cephalomedullary nailing for surgical fixation of complete fractures; avoidance of gaps in the lateral and anterior cortex; avoidance of varus malreduction.Cite this article: EFORT Open Rev 2018;3:494-500. DOI: 10.1302/2058-5241.3.170070.

Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis.

ContextDenosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis.ObjectiveDetermine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics.Design and SettingInternational, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension.PatientsPostmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points.InterventionsFREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years.OutcomesBone histology, histomorphometry, matrix mineralization.ResultsTen-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter.ConclusionsDenosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.

EFFECT OF ALENDRONATE ON THE HEALING TIME OF DISTAL RADIAL FRACTURES TREATED CONSERVATIVELY: AN OBSERVATIONAL STUDY

Objective: Although fragility fractures of the distal radius are common, osteoporosis treatment requires exploration as attempts to improve postfracture investigations have been only partially successful. Bisphosphonates may help minimize the risk of secondary fractures but being a potent antiresorptive agent; it raises concerns about adverse effects on the healing process. This observational study examines the effect of bisphosphonate (alendronate) on healing of acute fractures of distal radius through 66 patients aged &gt;45 years admitted to two tertiary care hospitals in Mangalore from May 2014 to September 2016.Methods: The methodology consists of purposive sampling from two groups: Control having 33 patients not on alendronate therapy and cases comprising 33 who are on alendronate as part of prophylaxis for osteoporosis before fracture occurrence, with outpatient reviews at 2-week intervals starting from the 6th till fracture union seen. At each visit, plain radiographs of the involved wrist were taken to yield time to cortical bridging, with range of active movement of the affected wrist taken using a goniometer. Data were analyzed using Statistical Package for the Social Sciences software version 17.0 for t values, p values and correlations and results were presented in the form of graphs and tables.Results: No significant differences were observed in the groups (as per p values) w.r.t. gender (0.804), age (0.835), time to healing (1.000), dorsiflexion (0.956), palmar flexion (0.670), ulnar deviation (0.441), radial deviation (1.000), supination (0.132), or pronation (0.302). Quick Disabilities of the Arm, Shoulder and Hand score did not differ by &gt;95% between the groups over the analysis period.Conclusion: It was observed that alendronate administration in distal radius fractures did not appear to delay fracture healing times radiologically or clinically.

Safety of long-term denosumab therapy for osteoporosis

Osteoporosis, characterised by progressive age-related increases in bone fragility and fracture risk, is a chronic condition that often requires many years of treatment. Data on safety and efficacy of drugs are provided by pivotal clinical trials, which are generally limited to 3 years duration; results of such studies cannot necessarily be extrapolated to longer treatment periods. Adverse effects might increase as a result of both ageing and cumulative drug exposure. Likewise, beneficial skeletal effects of the drug might not be maintained indefinitely. Furthermore, continued long-term suppression of bone turnover with potent antiresorptive agents could potentially result in weakened bone. Extension studies can provide useful information about effects of long-term treatment, although the absence of a placebo control group beyond the initial trial period, mandated by ethical considerations, and attenuation of the size of the treated population can reduce the robustness of the findings. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extensionDenosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Full-Text PDF

Retraction Note to: Efficacy of Antiresorptive Agents for Preventing Fractures in Japanese Patients with an Increased Fracture Risk: Review of the Literature.

The aim of the present review was to clarify the efficacy of currently available potent antiresorptive agents for preventing fractures in Japanese patients with an increased fracture risk. PubMed was used to search the literature for randomized controlled trials (RCTs), with the following search terms: fracture, etidronate, alendronate, risedronate, minodronate, raloxifene, bazedoxifene and Japan. The inclusion criteria were papers written in English, ≥50 subjects per group and a study period of ≥1 year. Fourteen RCTs met these criteria. The efficacy of antiresorptive agents for preventing vertebral, nonvertebral and hip fractures was investigated. There was evidence that raloxifene reduced the incidence of clinical vertebral fractures, while etidronate, alendronate and minodronate (but not bazedoxifene) reduced the incidence of morphometric vertebral fractures in patients with postmenopausal or involutional osteoporosis. Head-to-head trials showed that alendronate and raloxifene had similar efficacy for preventing vertebral fractures in patients with postmenopausal osteoporosis, while risedronate was not inferior to etidronate for reducing the incidence of morphometric vertebral fractures in patients with involutional osteoporosis. Alendronate reduced the incidence of hip fractures in patients with Parkinson's disease, and risedronate reduced the incidence of nonvertebral fractures and hip fractures in patients with Alzheimer's disease or stroke. In conclusion, the present review confirmed the efficacy of etidronate, minodronate and raloxifene for the prevention of vertebral fractures, the efficacy of alendronate for vertebral and hip fractures, and the efficacy of risedronate for vertebral, nonvertebral and hip fractures in Japanese patients with an increased fracture risk.

Effect of antiresorptive drugs in the alveolar bone healing. A histometric and immunohistochemical study in ovariectomized rats

The aim of this study is to evaluate the alendronate and raloxifene influence in the alveolar healing process of osteoporotic rats. Sixty-four female rats were divided in four groups: sham rats (SHAM), ovariectomized rats and no medical treatment (OVX NT), ovariectomized rats and submitted to alendronate treatment (OVX ALE), and ovariectomized and submitted to raloxifene treatment (OVX RAL). The histomorphometrical and immunohistochemical analysis was performed. The quantitative data were analyzed through Kruskal-Wallis and Dunn tests (α=0.05). In the longest period, SHAM and OVX RAL groups showed the better bone formation responses (P<0.05). The worst bone formation response was observed in the group OVX NT. OVX RAL group showed the better response at 42days. OVX ALE group showed a favorable response at 14days, in comparison with OVX RAL group, but a reduced response at 42days. It was possible to observe a mature bone in SHAM group at 14days and an immature bone in the OVX NT group. An intermediate quality bone was observed in the groups OVX ALE and OVX RAL. Alendronate and raloxifene treatment improved the alveolar healing process in osteoporotic rats, but not enough to achieve the histometrical and protein expression values that were observed in the SHAM group. Alendronate is largely used as a potent antiresorptive agent. Otherwise, considering the undesirable effects in relation to the alveolar healing, other antiosteoporosis medications should be studied. Raloxifene seems to be a good candidate once its action mechanism involves the activation of osteoblasts.

Modulation of paraoxonase 1 (PON1) activity and protein N-homocysteinylation by bisphosphonates in rats

Background and aimBisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. As osteoporosis and atherosclerosis share some common risk factors and frequently coexist in the same patients, we examined the effect of bisphosphonates on paraoxonase 1 (PON1) – the high density lipoprotein-associated enzyme with potent anti-atherosclerotic activity. Material and methodsBisphosphonates were administered orally to male adult rats for 4 weeks and then PON1 activity and some related biochemical parameters were measured in plasma. ResultsClodronate, alendronate, ibandronate and pamidronate reduced PON1 activity toward synthetic (paraoxon, phenyl acetate) and natural (homocysteine thiolactone) substrates. The most marked effect was observed in animals receiving ibandronate. In contrast, risedronate increased PON1 activity toward these 3 substrates and zoledronate increased PON1 activity toward phenyl acetate but had no effect on its activity toward paraoxon and homocysteine thiolactone. Bisphosphonates had no effect on total plasma homocysteine and protein-bound homocysteine thiolactone. In addition, total plasma cholesterol, HDL-cholesterol, plasma triglycerides and alanine aminotransferase activity did not differ between groups. ConclusionsBisphosphonates have differential effects on PON1 activity. Risedronate could be particularly useful in patients with high cardiovascular risk and PON1 deficiency. Bisphosphonates have no effect on plasma homocysteine and protein N-homocysteinylation as well as on the lipid profile.

Perspectives in the treatment and prevention of osteoporosis.

Osteoporosis is a chronic skeletal condition characterized by compromised bone strength. This disorder affects a substantial proportion of the elderly population and causes notable morbidity, deterioration in quality of life and mortality due to associated fragility fractures. Over the past two decades the range of therapeutic options for the treatment of osteoporosis and fracture prevention has increased dramatically with the development of potent antiresorptive and anabolic agents. This review summarizes the effects of existing treatment options and of promising new therapies for osteoporosis prevention and treatment.

Abstract P3-07-45: Bone turnover marker levels and clinical outcomes in patients with breast cancer and bone metastases treated with bone antiresorptive therapies

Abstract INTRODUCTION AND OBJECTIVES: Patients with advanced breast cancer (BC) and metastatic bone disease typically have elevated serum levels of bone turnover markers (BTMs). Potent antiresorptive agents, such as denosumab and zoledronic acid, can significantly reduce BTM levels (Stopeck et al. J Clin Oncol 2010). Prior studies have provided evidence that higher BTM baseline levels may be associated with worse clinical outcomes (Ali et al. Ann Oncol 2004). In this analysis, we assessed the association between BTM levels after treatment with antiresorptive agents and overall survival (OS), disease progression (DP) and disease progression in the bone (DPB) in patients with advanced BC and bone metastases. METHODS: This post-hoc analysis included data from patients with BC and bone metastases enrolled in an international, blinded phase 3 trial who were randomized to receive either denosumab (120 mg SC) or zoledronic acid (4 mg IV, adjusted for creatinine clearance). The BTMs urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BSAP) were measured at study entry and at study month 3. The clinical outcomes of OS, DP, and DPB were compared in patients with BTMs above or below median levels at month 3 of antiresorptive therapy. These covariate analyses were based on Cox models stratified by treatment, prior SRE before month 3, prior bisphosphonate use, chemotherapy at randomization, and region (Japan or other countries). RESULTS: A total of 1705 patients were measured for uNTx serum levels, with 895 patients ≥ and 810 &amp;lt; the median of 10.40 nmol/mmol at month 3. Similarly, BSAP levels were measured in a total of 1708 patients, with 855 patients ≥ and 853 &amp;lt; the median BSAP level of 10.89 ng/mL at month 3. Patients with uNTx levels ≥ the median at month 3 had a significantly reduced OS (by 54%) and a greater risk of both DP (by 21%) and DPB (by 23%) than patients with uNTx levels &amp;lt; median (see Table). Similarly, patients with BSAP levels ≥ the median level at month 3 had an increased risk for reduced OS (by 197%), DP (by 67%) and DPB (by 56%) compared with patients whose BSAP levels &amp;lt; median. After adjusting for risk factors suggestive of more advanced disease such as visceral metastases or &amp;gt; 2 bone metastases, the correlation between elevated BTMs and reduced OS and greater risk of DP and DPB was maintained. CONCLUSIONS: Patients with BTM levels ≥ median at month 3 of antiresorptive therapy had generally worse clinical outcomes than patients whose BTM levels were &amp;lt; median. Assessment of uNTx and BSAP serum levels after treatment with antiresorptive therapy can add to our understanding of which patients with breast cancer and bone metastases are most at risk for decreased OS, or increased DP or DPB. Month 3*Covariate Analysis Results: Risk of Decreased OS or Increased DP or DPBClinical OutcomeHazard Ratio (95% Confidence Interval)P-valueDecrease in OSuNTXa1.539 (1.270, 1.866)&amp;lt;0.0001BSAPb2.966 (2.422, 3.633)&amp;lt;0.0001Increase in DPuNTXa1.214 (1.071, 1.377)=0.0024BSAPb1.666 (1.470, 1.888)&amp;lt;0.0001Increase of DPBuNTXa1.231 (1.054, 1.437)=0.0087BSAPb1.563 (1.342, 1.821)&amp;lt;0.0001*Comparing ≥ median to &amp;lt; median. aMedian uNTx levels=10.40 nmol/mmol. bMedian BSAP level=10.89 ng/mL. Citation Format: Lipton A, Stopeck A, Body J-J, Von Moos R, De Boer R, Paiva Gadelha Guimaraes A, Tonkin K, Fujiwara Y, Zhu L, Warner D. Bone turnover marker levels and clinical outcomes in patients with breast cancer and bone metastases treated with bone antiresorptive therapies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-45.

ENDOCRINOLOGY AND ADOLESCENCE: Osteoporosis in children: diagnosis and management.

Osteoporosis in children can be primary or secondary due to chronic disease. Awareness among paediatricians is vital to identify patients at risk of developing osteoporosis. Previous fractures and backaches are clinical predictors, and low cortical thickness and low bone density are radiological predictors of fractures. Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary paediatric units with the necessary multidisciplinary expertise. Modern OI management focuses on functional outcomes rather than just improving bone mineral density. While therapy for OI has improved tremendously over the last few decades, this chronic genetic condition has some unpreventable, poorly treatable and disabling complications. In children at risk of secondary osteoporosis, a high degree of suspicion needs to be exercised. In affected children, further weakening of bone should be avoided by minimising exposure to osteotoxic medication and optimising nutrition including calcium and vitamin D. Early intervention is paramount. However, it is important to identify patient groups in whom spontaneous vertebral reshaping and resolution of symptoms occur to avoid unnecessary treatment. Bisphosphonate therapy remains the pharmacological treatment of choice in both primary and secondary osteoporosis in children, despite limited evidence for its use in the latter. The duration and intensity of treatment remain a concern for long-term safety. Various new potent antiresorptive agents are being studied, but more urgently required are studies using anabolic medications that stimulate bone formation. More research is required to bridge the gaps in the evidence for management of paediatric osteoporosis.

Gastroretentive Floating Capsules of Risedronate Sodium: Development, Optimization, in vitro and in vivo Evaluation in Healthy Human Volunteers

Background and the purpose of the study: Risedronate sodium inhibits osteoclast bone resorption and modulates bone metabolism. Risedronate has a high affinity for hydroxyapatite crystals in bone and is a potent antiresorptive agent. In the present investigation efforts were made to improve the bioavailability of risedronate sodium by increasing the residence time of the drug through sustained-release matrix capsule formulation via gastroretentive mechanism. Capsules were prepared by wet granulation technique. The influence of gel forming agents, amount of risedronate and total weight of capsules on physical properties, in vitro buoyancy, drug release, FTIR, DSC, X-ray studies were investigated. The release mechanisms were explored and explained by applying zero order, first order, Higuchi and Korsmeyer equations. The selected formulations were subjected to stability study at 40 °C/75% RH, 25 °C/60% RH for the period of three months. For all formulations, kinetics of drug release from capsules followed Higuchi’s square root of time kinetic treatment heralding diffusion as predominant mechanism of drug release. Formulation containing 25 mg HPMC K4M and 75 mg HPMC K100 LV (F-8) showed zero order release profile. There was no significant change in the selected formulation, when subjected to accelerated stability conditions over a period of three months. X-ray imaging in six healthy human volunteers revealed a mean gastric retention period of 5.60 ± 0.77 hrs for the selected formulation. Stable, sustained release effervescent floating capsules of risedronate sodium could be prepared by wet granulation technique.&#x0D;

Immune regulation of bone metastasis.

Metastases to bone occur in about 70% of patients with metastatic prostate and breast cancers. Unfortunately, bone metastases result in significant morbidity and mortality and treatment options are limited. Thus, significant effort has focused on understanding the mechanisms that drive tumor dissemination to bone. Bone metastases are typically characterized by a self-perpetuating 'vicious' cycle wherein tumor cells and bone-resorbing cells (osteoclasts) are locked in a cycle that leads to osteoclast-driven bone destruction and the release of bone-stored factors that in turn stimulate tumor cell proliferation and survival. To break this 'vicious' cycle, potent antiresorptive agents such as zoledronic acid (ZOL) have been used. However, in the clinical setting, ZOL failed to improve the overall survival of cancer patients even though it inhibited osteoclast resorptive activity. Thus, other cells in addition to osteoclasts are likely involved in modulating tumor growth in the bone. The immune system has the ability to eliminate tumor cells. Nevertheless, tumor cells can acquire the ability to escape immune control. Our recent observations indicated that a decline in the ability of the immune cells to recognize and kill the tumor drives tumor dissemination to bone even when osteoclasts are inhibited by potent antiresorptive agents. This review focuses on the antitumor and protumor effects of various immune cell populations involved in the bone metastatic process. We also discuss strategies to enhance antitumor immune responses and bypass cancer immune resistance.

Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches.

In the recent Bone Key Reports review, it was noted that combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent as monotherapy. Small clinical trials have been performed evaluating combinations of PTH1-34 (TPTD) or PTH1-84 (PTH) with a variety of antiresorptives including hormone/estrogen therapy, raloxifene, alendronate, risedronate, ibandronate, zoledronic acid, and denosumab. Most of the studies evaluate dual-energy X-ray absorptiometry outcomes, and a few trials report volumetric mineral density (BMD) by quantitative computed tomography, followed by finite element modeling to calculate bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary based on the timing of introduction of the anabolic agent (before, during, or after antiresorptive treatment), as well as the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site-dependent. The most consistent effect of combining antiresorptive agents with PTH or TPTD is a superior hip BMD outcome compared with TPTD/PTH alone. This is most evident when TPTD/PTH is combined with a bisphosphonate or denosumab. In contrast to findings in the hip, in the majority of studies, there is no benefit to spine BMD with combination therapy vs monotherapy. The 2 exceptions to this are when TPTD is combined with denosumab and when TPTD is given as monotherapy first for 9 months, followed by the addition of alendronate (with continuation administration of TPTD). Based on what we now know, in patients previously treated with bisphosphonates who suffer hip fractures or who have very low or declining hip BMD, strong consideration should be given to starting TPTD and continuing a potent antiresorptive agent (possibly switching to zoledronic acid or denosumab) to improve hip BMD and strength quickly. Furthermore, in treatment naïve individuals with very severe osteoporosis, such as those with spine and hip fractures, combination therapy with TPTD and denosumab or TPTD followed by combination treatment with a potent bisphosphonate or denosumab should be considered to maximize early increases in BMD throughout the skeleton (Cosman BoneKEy Rep 3, 2014).

The role of teriparatide in sequential and combination therapy of osteoporosis.

Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.

Intravenous Zoledronate for a Patient with Paget's Disease

Paget's disease (PD) of bone is characterized by increase of bone resorption by atypical osteoclasts, followed by rapid new bone formation resulting in a disorganized mosaic bone. Although the pathophysiology is not fully understood, bisphosphonate, which is a potent anti-resorptive agent for treatment of osteoporosis, have been the most effective agents available for the treatment of PD. We report a case of PD of bone in a 49-year-old woman patient, who was treated with intravenous zoledronate.

Bone Histomorphometry of Transiliac Paired Bone Biopsies After 6 or 12 Months of Treatment With Oral Strontium Ranelate in 387 Osteoporotic Women: Randomized Comparison to Alendronate

Preclinical studies indicate that strontium ranelate (SrRan) induces opposite effects on bone osteoblasts and osteoclasts, suggesting that SrRan may have a dual action on both formation and resorption. By contrast, alendronate (ALN) is a potent antiresorptive agent. In this multicenter, international, double-blind, controlled study conducted in 387 postmenopausal women with osteoporosis, transiliac bone biopsies were performed at baseline and after 6 or 12 months of treatment with either SrRan 2 g per day (n = 256) or alendronate 70 mg per week (n = 131). No deleterious effect on mineralization of SrRan or ALN was observed. In the intention-to-treat (ITT) population (268 patients with paired biopsy specimens), changes in static and dynamic bone formation parameters were always significantly higher with ALN compared with SrRan at month 6 (M6) and month 12 (M12). Static parameters of formation were maintained between baseline and the last value with SrRan, except for osteoblast surfaces, which decreased at M6. Significant decreases in the dynamic parameters of formation (mineralizing surface, bone formation rate, adjusted apposition rate, activation frequency) were noted at M6 and M12 in SrRan. Compared with ALN, the bone formation parameters at M6 and M12 were always significantly higher (p < 0.001) with SrRan. ALN, but not SrRan, decreased resorption parameters. Compared with the baseline paired biopsy specimens, wall thickness was significantly decreased at M6 but not at M12 and cancellous bone structure parameters (trabecular bone volume, trabecular thickness, trabecular number, number of nodes/tissue volume) were significantly decreased at M12 with SrRan; none of these changes were significantly different from ALN. In conclusion, this large controlled paired biopsy study over 1 year shows that the bone formation remains higher with a lower diminution of the bone remodeling with SrRan versus ALN. From these results, SrRan did not show a significant anabolic action on bone remodeling.

Comparative Effect of Zoledronic Acid Versus Denosumab on Serum Sclerostin and Dickkopf-1 Levels of Naive Postmenopausal Women With Low Bone Mass: A Randomized, Head-to-Head Clinical Trial

Decreased bone formation due to a coupling effect limits bone mass increases after antiresorptive treatment. The purpose of this study was to compare the effects of 2 potent antiresorptive agents with different mechanism of action on serum levels of Wnt antagonists, sclerostin and dickkopf-1 (Dkk-1). This was an interventional, parallel assignment, open-label, randomized clinical trial. The study was conducted at the outpatient clinics for metabolic bone diseases of 424 General Military Hospital, Thessaloniki, Greece. Naive postmenopausal women with low bone mass were assigned to zoledronic acid infusion (n = 46) or denosumab injection (n = 46). One woman in the zoledronic acid group was lost to follow-up. Serum sclerostin and Dkk-1 levels were the main outcomes. Secondary measurements were serum osteoprotegerin, receptor activator of nuclear factor κB ligand, procollagen type 1 N-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen. Serum sclerostin levels significantly decreased in the zoledronic acid (P < .001) but increased in the denosumab group (P = .003). Dkk-1 levels significantly decreased in the zoledronic acid group (P = .006) but did not change in the denosumab group (P = .402). Serum osteoprotegerin remained essentially unchanged in either group, whereas receptor activator of nuclear factor κB ligand decreased in the zoledronic acid group (P = .004) but increased in the denosumab group (P = .037). Bone markers (procollagen type 1 N-terminal propeptide, C-terminal cross-linking telopeptide of type 1 collagen, and total serum alkaline phosphatase) decreased in both groups (all P < .001). Although they both decrease bone resorption, zoledronic acid and denosumab exert opposite effects on Wnt signaling: the former decreases serum levels of both sclerostin and Dkk-1, whereas the latter increases sclerostin and does not affect Dkk-1.