Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin

The benefits coming from long-term treatment of postmenopausal osteoporosis with bisphophonates are limited by a coupled decrease in bone formation. The objective of this study is to determine whether this decrease in bone formation is associated with changes in serum levels of the WNT signaling antagonist sclerostin or Dickkopf-1 (DKK1). This is an ancillary observation from patients participating in a 12 months, phase 2, randomized clinical trial. We analyzed 107 patients given either monthly intramuscular neridronate (12.5, 25 or 50 mg) or placebo. Serum C-terminal telopeptide of type I collagen (sCTX, a bone-resorption marker) decreased by 61%, 75% and 73% in the 12.5, 25 and 50 mg dose groups, respectively. Mean changes in bone alkaline phosphatase (bAP) at 12 months were -47%, -60.0% and -52.6% in the groups receiving 12.5, 25 or 50 mg neridronate, respectively. Serum DKK1 remained unchanged at all time points in the 3 groups. Serum sclerostin increased versus placebo group gradually and significantly only in patients treated with 25 or 50 mg neridronate monthly, reaching 138-148% of baseline values (P<0.001). Changes in serum sclerostin at 12 months were negatively correlated with changes in bAP (P<0.001) even when data were adjusted for sCTX changes and only treated patients were included. In conclusions, decreased bone formation after several months of bisphosphonate therapy is associated with increased serum levels of sclerostin. This might suggest that Wnt signaling may play a role in the coupling between resorption and formation.     

Sclerostin and DKK1 in Primary Hyperparathyroidism

Bone formation is influenced by the Wnt pathway through effects on osteoblast functionality, and these actions are opposed by two antagonists: sclerostin and Dickkopf-1 (DKK1). Decreased levels of serum sclerostin were found after treatment with the PTH analogue teriparatide and in patients with primary hyperparathyroidism (PHPT), while treatment with teriparatide of postmenopausal osteoporosis is associated with increases in serum DKK1. We studied mineral metabolism and Wnt pathway in 21 postmenopausal women affected by PHPT and in 42 age-matched healthy women. Mean serum calcium and PTH were significantly higher and serum phosphates significantly lower in the PHPT group compared with the control group. Serum 25-OH-vitamin D (25OHD) was lower in PHPT patients and 1,25 dihydroxy-vitamin D [1,25(OH)₂D] was significantly higher. Patients with PHPT had significantly higher levels of bone alkaline phosphatase (BAP) and of serum C-terminal telopeptides of type I collagene (sCTX). Serum sclerostin in PHPT was significantly lower (?26 %) and serum DKK1 significantly higher (+57 %) than in healthy control subjects. Serum PTH was positively correlated with 1,25OH₂D (p < 0.001), BAP (p = 0.036), sCTX (p = 0.003), and DKK1 (p = 0.007) and negatively with 25OHD (p = 0.002) and sclerostin (p = 0.02). In PHPT patients, serum sclerostin was negatively correlated with BAP (p = 0.038) and sCTX (p = 0.07). Patients with PHPT have significantly lower sclerostin and higher DKK1 levels compared with healthy postmenopausal control subjects. Further studies are warranted in order to verify whether the balance between these two opposite effects on Wnt function might help explain the variable bone involvement among patients with PHPT.     

Teriparatide Treatment in Adult Patients with Osteogenesis Imperfecta Type I

Osteogenesis imperfecta (OI) is a hereditary disease characterized by low bone mass, increased bone fragility, short stature, and skeletal deformities. This study focuses on OI type I, the mildest form of the disease. Bisphosphonates represent the prevailing standard of care in patients with OI. Teriparatide (TPD) is a PTH analog with bone-anabolic actions which has been approved for osteoporosis treatment. Thirteen postmenopausal women with type I OI who had been on treatment with neridronate for at least 2 years and who incurred new vertebral fracture during treatment were treated with TPD for 18 months. Bone mineral density (BMD) increased significantly over 18 months up to 3.5 % at the lumbar spine (p = 0.001), while no significant changes were noted in hip BMD. Serum markers of bone formation and of bone resorption increased significantly during the treatment. The Wnt inhibitors serum dickkopf-1 (DKK1) and sclerostin were also measured. A nonsignificant increase was seen in serum sclerostin levels, while serum DKK1 rose gradually and significantly during TPD treatment. In patients affected by type I OI, TPD treatment is associated with a remarkable response in markers of bone formation. This suggests a normal osteoblastic response to TPD. However, the observed increases in BMD were somewhat lower than those in postmenopausal or senile osteoporosis treated with TPD for the same lag time. Our results open the possibility to develop TPD for the treatment of adult type I OI, but particularly for the lack of a control group, a properly designed controlled study is warranted.     

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.     

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy

Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double‐blind, double‐dummy study in 504 postmenopausal women ≥ 55 years of age with a BMD T‐score of ?2.0 or less and ?4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open‐label branded alendronate 70 mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60 mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p < .0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p < .0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p < .0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups. Copyright © 2010 American Society for Bone and Mineral Research     

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab

Romosozumab is a bone‐forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In FRActure study in postmenopausal woMen with ostEoporosis (FRAME), postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T‐score changes from baseline over the 2‐year study and contrast these results with the long‐term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab‐treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T‐score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo‐to‐denosumab: 0.38 and 0.17), with the 2‐year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive therapy. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

The Effect of Discontinuing Treatment With Blosozumab: Follow‐up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1‐year randomized, placebo‐controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow‐up; 88 women completed 1 year of follow‐up. At the beginning of follow‐up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow‐up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow‐up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C‐terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti‐drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Perspective: Assessing the Clinical Utility of Serum CTX in Postmenopausal Osteoporosis and Its Use in Predicting Risk of Osteonecrosis of the Jaw

Bone turnover markers (BTMs) have become increasingly important in the management of postmenopausal osteoporosis (PMO). In bisphosphonate‐treated women with PMO, BTMs can provide early indications of treatment efficacy, are predictors of BMD response and fracture risk reduction, and are potentially useful for monitoring patient compliance. The bone resorption marker serum C‐telopeptide cross‐link of type 1 collagen (sCTX) has shown high sensitivity and specificity for the detection of increased bone resorption. Recently, sCTX has been singled out as a potential indicator of risk of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates who require oral surgery. However, whether BTMs are capable of predicting ONJ risk and whether sCTX is usable for this purpose are controversial questions. This article presents an overview of the current literature regarding critical issues affecting the clinical utility of BTMs (including variability and reference ranges) and the current applications of BTMs in PMO management, with a focus on sCTX. Last, the appropriateness of using sCTX to predict ONJ risk in women receiving oral bisphosphonates for PMO is evaluated.     

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized,Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ ?2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.     

Distinct effect of zoledronate and clodronate on circulating levels of DKK1 and sclerostin in women with postmenopausal osteoporosis

The coupling of bone formation to bone resorption during treatment of postmenopausal osteoporosis with antiresorbers might be related to changes in Wnt/b-catenin signaling. We compared the effects of two bisphosphonate treatments on two Wnt-inhibitors Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1).The study population included 74 women with postmenopausal osteoporosis participating simultaneously in two multicenter, placebo controlled trials. The patients were randomized to: intramuscular clodronate 100 mg/week (CLO) (N = 36), and yearly intravenous therapy with 5 mg zoledronate (ZOL) (N = 18) and placebo (N = 20).Bone turnover markers (intact N-propeptide of type I collagen [P1NP], C-terminal telopeptide of type I collagen [CTX]) remained unchanged in the placebo group while they significantly decreased during treatment with the two bisphosphonates, versus both placebo and baseline. In CLO treated patients serum DKK1 remained stable over the entire period of observation while serum SOST levels increased significantly after 12 months of treatment both versus placebo group (p < 0,005), baseline (p < 0,001) and ZOL treated group.In the ZOL group, DKK1 levels increased significantly within one month and for the following 6 months and it fell back to baseline values at 12 months. The second ZOL infusion was again associated with an increase in DKK1 a month later, although to a lesser extent.In conclusion, in this study we have found that the treatment of postmenopausal osteoporosis with intermittent yearly ZOL is associated with transient and declining increases in DKK1 while continuous treatment with CLO, results in a late increase in serum SOST. These preliminary results and further ad hoc studies might contribute to shed light on our understanding of the bone coupling effects taking place during treatment of osteoporosis with different anti-resorbers or with different treatment regimens.     

A Randomized,Double‐Blind Phase 2 Clinical Trial of Blosozumab,a Sclerostin Antibody,in Postmenopausal Women with Low Bone Mineral Density

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double‐blind, placebo‐controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T‐score –2.0 to –3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T‐score –2.8). Blosozumab treatment resulted in statistically significant dose‐related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest‐dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

Bone remodeling in postmenopausal women who discontinued denosumab treatment: Off‐treatment biopsy study

Denosumab is a fully human monoclonal antibody that neutralizes the activity of RANKL, leading to the inhibition of osteoclast maturation, bone‐resorbing activity, and survival. Evaluation of trans–iliac crest bone biopsy specimens in the phase 3 pivotal fracture study with denosumab in postmenopausal women with osteoporosis showed evidence of reduced bone turnover at the tissue level in subjects receiving denosumab, and up to one‐third of subjects did not have evidence of tetracycline labeling in trabecular or cortical bone. Discontinuation of denosumab therapy has demonstrated that the effects of denosumab are reversible, as assessed by biochemical markers of bone turnover (BTM) and BMD. The precise nature of changes that occur at the tissue level with denosumab discontinuation have not been explored. Fifteen subjects were enrolled in a cohort study to evaluate the effects of denosumab discontinuation at the tissue level. Subjects had discontinued osteoporosis treatment for a mean time of 25.1 months (range 21 to 29 months). Bone histomorphometry results were compared with results from placebo‐treated women with osteoporosis in the denosumab phase 3 pivotal fracture bone biopsy substudy, and BTMs were compared with subjects' pretreatment values. The results of this study showed normal histology and bone remodeling similar to those observed in untreated postmenopausal women with osteoporosis. With treatment cessation, 100% of biopsy specimens had evidence of tetracycline labels. Biochemical markers were comparable to and highly correlated with pretreatment levels. These data confirm that the effects of denosumab on bone turnover at the tissue level are fully reversible. © 2011 American Society for Bone and Mineral Research     

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. © 2011 American Society for Bone and Mineral Research     

High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: The center of excellence for osteoporosis research study

Sclerostin regulates bone formation by inhibiting Wnt pathway signaling. Low circulating sclerostin levels cause high bone mass. We hypothesized that postmenopausal women with increased sclerostin levels have a greater risk for osteoporosis‐related fractures. We examined the association between circulating sclerostin together with bone turnover markers and osteoporosis‐related fracture risk in 707 postmenopausal women, in a population‐based study with a mean follow‐up period of 5.2 ± 1.3 years. Multivariate Cox proportional hazards regression models were used to analyze fracture risk, adjusted for age, body mass index, and other confounding risk factors. High sclerostin levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the relative fracture risk was more than sevenfold among postmenopausal women for each 1‐SD increment increase in sclerostin level. Women in the highest quartile of sclerostin levels had about a 15‐fold increase in fracture risk. Results were similar when we compared sclerostin at the 1‐year visit to an average of two to three annual measurements. Fracture risk attributable to sclerostin levels was 56.6% in the highest quartile. Only high levels of bone resorption markers (plasma cross‐linked C‐terminal telopeptide of type 1 collagen [p‐CTx], urinary CTx [u‐CTx], and urinary N‐telopeptide of type 1 collagen [u‐NTx]) were predictive of osteoporosis‐related fractures but at much lower hazard ratio (HR) values than that of serum sclerostin. Associations between sclerostin levels and fracture risk were independent of bone mineral density and other confounding risk factors. High sclerostin levels are a strong and independent risk factor for osteoporosis‐related fractures among postmenopausal women. © 2012 American Society for Bone and Mineral Research.     

Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension

The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a "virtual untreated twin" cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.     

Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD.

Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo-controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women. INTRODUCTION: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD. MATERIALS AND METHODS: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of -1.8 to -4.0 or femoral neck/total hip T-scores of -1.8 to -3.5 were randomly assigned to receive double-blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety. RESULTS: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and > or =60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment. CONCLUSIONS: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo.     

Effects of strontium ranelate on bone mass and bone turnover in women with thalassemia major-related osteoporosis

Subjects affected by thalassemia major (TM) often have reduced bone mass and increased fracture risk. Strontium ranelate (SrR) is an effective treatment for postmenopausal and male osteoporosis. To date, no data exist on the use of SrR in the treatment of TM-related osteoporosis. Our aim was to evaluate the effects of SrR on bone mineral density (BMD), bone turnover markers and inhibitors of Wnt signaling (sclerostin and DKK-1). Twenty-four TM osteoporotic women were randomized to receive daily SrR 2 g or placebo in addition to calcium carbonate (1,000 mg) and vitamin D (800 IU). BMD at the lumbar spine and femoral neck, bone turnover markers (C-terminal telopeptide of procollagen type I [CTX], bone-specific alkaline phosphatase [BSAP]) and insulin-like growth factor-1 (IGF-1), sclerostin and DKK-1 were assessed at baseline and after 24 months. Back pain was measured by visual analog scale (VAS) every 6 months. After 24 months, TM women treated with SrR had increased their spine BMD values in comparison to baseline (p < 0.05). Moreover, they also exhibited a reduction of CTX and sclerostin levels (but not DKK-1) and exhibited an increase of BSAP and IGF-1 (p < 0.05); however, no significant changes were observed in the placebo group. In the SrR group, a reduction of back pain was observed after 18 months in comparison to baseline (p < 0.05) and after 24 months in comparison to placebo (p < 0.05). Our study reports for the first time the effects of SrR in the treatment of TM-related osteoporosis. SrR treatment improved BMD and normalized bone turnover markers, as well as lowering sclerostin serum levels.     

Methylation of Bone SOST,Its mRNA,and Serum Sclerostin Levels Correlate Strongly With Fracture Risk in Postmenopausal Women

Inhibition of sclerostin, a glycoprotein secreted by osteocytes, offers a new therapeutic paradigm for treatment of osteoporosis (OP) through its critical role as Wnt/catenin signaling regulator. This study describes the epigenetic regulation of SOST expression in bone biopsies of postmenopausal women. We correlated serum sclerostin to bone mineral density (BMD), fractures, and bone remodeling parameters, and related these findings to epigenetic and genetic disease mechanisms. Serum sclerostin and bone remodeling biomarkers were measured in two postmenopausal groups: healthy (BMD T‐score > –1) and established OP (BMD T‐score < –2.5, with at least one low‐energy fracture). Bone specimens were used to analyze SOST mRNAs, single nucleotide polymorphisms (SNPs), and DNA methylation changes. The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively). Serum sclerostin and bone SOST mRNA expression correlated positively with age‐adjusted and BMI‐adjusted total hip BMD (r = 0.47 and r = 0.43, respectively; both p < 0.0005), and inversely to serum bone turnover markers. Five SNPs, one of which replicates in an independent population‐based genomewide association study (GWAS), showed association with serum sclerostin or SOST mRNA levels under an additive model (p = 0.0016 to 0.0079). Genetic and epigenetic changes in SOST influence its bone mRNA expression and serum sclerostin levels in postmenopausal women. The observations suggest that increased SOST promoter methylation seen in OP is a compensatory counteracting mechanism, which lowers serum sclerostin concentrations and reduces inhibition of Wnt signaling in an attempt to promote bone formation. © 2014 American Society for Bone and Mineral Research.     

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension

Denosumab is a fully human monoclonal antibody against receptor activator of NF‐κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3‐year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low‐frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3‐year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long‐term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low‐frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.     

Effects of Denosumab and Teriparatide Transitions on Bone Microarchitecture and Estimated Strength: the DATA‐Switch HR‐pQCT study

In postmenopausal osteoporosis, switching from teriparatide to denosumab results in continued bone mineral density (BMD) gains whereas switching from denosumab to teriparatide results in BMD loss. To assess the effects of these transitions on bone microarchitecture and strength, we performed high‐resolution peripheral QCT (HR‐pQCT) at the distal tibia and radius in postmenopausal osteoporotic women who received 24 months of teriparatide 20 μg daily followed by 24 months of denosumab 60 mg every 6 months, 24 months of denosumab followed by 24 months of teriparatide, or 24 months of both medications followed by 24 months of denosumab. The 77 women who completed at least one post‐switch visit are included in this analysis. Tibial cortical volumetric BMD (vBMD) increased between months 24 and 48 in the teriparatide‐to‐denosumab (net 48‐month change –0.8% ± 2.4%) and combination‐to‐denosumab groups (net 48‐month changes +2.4% ± 4.1%) but decreased in the denosumab‐to‐teriparatide group (net 48‐month change –3.4% ± 3.2%, p < 0.001 for all between‐group comparisons). Changes in total vBMD, cortical thickness, and estimated stiffness (by micro–finite element analysis [µFEA]) followed a similar pattern, as did changes at the radius. Conversely, tibial cortical porosity remained stable between months 24 and 48 in the teriparatide‐to‐denosumab and combination‐to‐denosumab groups (net 48‐month changes +7.2% ± 14.8% and –3.4% ± 12.1%, respectively) but increased in the denosumab‐to‐teriparatide group (net 48‐month change +16.2% ± 11.5%, p < 0.05 versus other groups). Trabecular vBMD changes did not differ among groups. Together, these findings demonstrate that in women treated with denosumab, switching to teriparatide is associated with a reduction in total and cortical vBMD, cortical thickness, and estimated strength, whereas switching to denosumab from teriparatide or combination therapy results in improvements in these parameters with the greatest improvements observed in women treated with combined therapy followed by denosumab. These findings strongly suggest that the use of teriparatide after denosumab should be avoided and that the use of combined teriparatide/denosumab followed by denosumab alone may be a useful treatment strategy in those with severe osteoporosis. © 2017 American Society for Bone and Mineral Research.