Reduced Bone Turnover Markers Research Articles

Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women.

Epidemiological studies indicate that higher bone mass is associated with moderate alcohol consumption in postmenopausal women. However, the underlying cellular mechanisms responsible for the putative beneficial effects of alcohol on bone are unknown. Excessive bone turnover, combined with an imbalance whereby bone resorption exceeds bone formation, is the principal cause of postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause. Bone mineral density was determined by dual-energy x-ray absorptiometry in 40 healthy postmenopausal women (mean ± SE age, 56.3 ± 0.5 y) who consumed alcohol at 19 ± 1 g/day. Serum levels of the bone formation marker osteocalcin and the resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and after alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed on the following morning. Bone mineral density at the trochanter and total hip were positively correlated to the level of alcohol consumption. Serum osteocalcin and CTx increased after abstinence (4.1 ± 1.6%, P = 0.01 and 5.8 ± 2.6%, P = 0.02 compared with baseline, respectively). Osteocalcin and CTx decreased after alcohol readministration, compared with the previous day (-3.4 ± 1.4%, P = 0.01 and -3.5 ± 2.1%, P = 0.05, respectively), to values that did not differ from baseline (P > 0.05). Abstinence from alcohol results in increased markers of bone turnover, whereas resumption of alcohol reduces bone turnover markers. These results suggest a cellular mechanism for the increased bone density observed in postmenopausal moderate alcohol consumers. Specifically, the inhibitory effect of alcohol on bone turnover attenuates the detrimental skeletal consequences of excessive bone turnover associated with menopause.

Eldecalcitol normalizes bone turnover markers regardless of their pre-treatment levels

Background:Three-year treatment with eldecalcitol has been shown to improve lumbar and total hip bone mineral density (BMD), decrease bone turnover markers, and lower the incidences of vertebral and wrist fractures in patients with osteoporosis more than with treatment with alfacalcidol under vitamin D repletion. The purpose of this study was to determine whether there was a risk of eldecalcitol causing severely suppressed bone turnover in osteoporosis patients with low pre-treatment levels of bone turnover markers.Methods and results:Post-hoc analysis was conducted on the data from a 3-year, randomized, double-blind, active-comparator, clinical trial of eldecalcitol versus alfacalcidol under vitamin D repletion conducted in Japan. Enrolled patients with baseline measurements of bone turnover markers were stratified into tertiles according to their pre-treatment levels of serum bone-specific alkaline phosphatase, serum procollagen type I N-terminal propeptide, or urinary collagen-N-telopeptide. Eldecalcitol treatment rapidly reduced bone turnover markers, and kept them within the normal range. However, in the patients whose baseline values for bone turnover were low, eldecalcitol treatment did not further reduce bone turnover markers during the 3-year treatment period. Further long-term observation may be required to reach the conclusion.ClinicalTrials.gov number:Trial registration: ClinicalTrials.gov identifier: NCT00144456.Conclusions:Eldecalcitol normalizes, but does not overly suppress, bone turnover regardless of baseline levels of bone turnover markers. Thus, it is unlikely that eldecalcitol treatment will increase the risk of severely suppressed bone turnover and therefore deterioration of bone quality, at least for a treatment duration of 3 years.

Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial

SummaryIn a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study.IntroductionThe purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.MethodsIn the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.ResultsOf the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.ConclusionContinued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.

Modulation of bone turnover in orchidectomized rats treated with raloxifene and risedronate

Osteoporosis is a reduction in bone mineral density (BMD). It develops less often in men than in women. This study aimed to evaluate the bone protective effects of raloxifene (RAL), risedronate (RIS), and their combination on osteoporotic male rats. Forty male Wister rats (12 weeks) were randomly divided into five groups: sham-operated group (n = 8), orchidectomized (ORX) group (n = 7), RAL group (n = 9), RIS group (n = 7) and RAL + RIS group (n = 7). RAL was orally administered at 3 mg/kg three times/week, and RIS was given subcutaneously at 5 μg/kg, twice weekly. After 6 weeks of treatment, serum cathepsin-K, alkaline (ALP) and acid phosphatase activities, serum osteocalcin, serum Ca²⁺, and Pi were determined. Urinary Ca²⁺ and deoxypyridinoline levels, BMD, and Ca²⁺ content of femur ash were estimated. Histochemical localization of ALP activity of tibia and histomorphometry was examined. As compared to sham, ORX rats showed a significant increase in bone turnover markers, and histochemical activity of ALP was increased markedly in proximal tibia of ORX rats, whereas BMD and Ca²⁺ content of femur ash were reduced after ORX. These changes were modulated after treatment with RAL and RIS or both to ORX rats; BMD of femur was improved by each treatment, and bone turnover markers were reduced as compared to ORX vehicle group. We concluded that orchidectomy induced osteoporosis and increased bone turnover in male rats because of withdrawal of sex hormones. Both RAL and RIS could treat osteoporosis in ORX rats; they reduced bone turnover markers and maintained BMD.

Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).

4513 Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of bone scan resolution, pain relief and overall disease control, independent of PSA changes, were previously reported in a phase II study in mCRPC patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a novel primary endpoint of bone scan response based on computer-aided quantitative assessment of bone scan lesion area (BSLA) and a double-reader, independent, blinded review (Nucl Med Commun, in press). Methods: D-pretreated (≥225 mg/m2) CRPC pts with bone metastasis were required to have progressed in soft-tissue or bone within 6 months of last dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6 wks. Bone scan response (BSR) was defined by a ≥30% decline in BSLA. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and interference with sleep and daily activity were prospectively assessed using an IVR system. Analgesic use was collected by diary. Bone turnover markers and CTCs were assessed. Results: 93 D-pretreated pts were enrolled (89 evaluable with ≥6 wks f/u). Median age was 67, 46% received cabazitaxel and/or abiraterone, 32% had visceral disease, 51% had fatigue, and 18% had anemia. 44% had worst pain ≥4 of which 95% were taking narcotics. Median CTC count was 49 and 80% had ≥5. Median f/u was 125 days (range, 23-305). Of 85 pts evaluable for BSR, 51 (60%) had a PR, 24 (28%) SD, 5 (6%) PD and 5 (6%) d/c’d prior to f/u scan. 21/30 pts (70%) had reduction of measurable disease.16/33 pts (49%) with BPI ≥4 and ≥12 wks f/u had pain reduction durable for ≥6 wks; 46% had decreased narcotic use, including 27% who discontinued use. Sleep and daily activity were improved in pts with pain relief. Among pts with elevated serum levels, 74%, 67% and 47% had declines on treatment of ≥30% in CTx, NTx and bALP, respectively. In 59 pts with CTCs ≥5, 92% had a decrease of ≥30% and 39% converted to <5 CTCs at weeks 6 or 12. 12% discontinued cabo due to AEs. Most common Gr 3/4 AEs were fatigue (19%), nausea (10%) and anemia (10%). Conclusions: Cabo treatment resulted in high rates of bone scan response, durable pain relief, and reductions in bone turnover markers and CTCs in D-pre-treated CRPC pts with bone metastases.

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head "offset" data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies.

Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature

We undertook a systematic review of the literature concerning the efficacy and safety of bisphosphonates in acute Charcot neuropathic osteoarthropathy. MEDLINE, PubMed, the Cochrane Database of Systematic Reviews, and abstracts presented during the meetings of the American Diabetes Association and the European Association of Diabetes were searched for relevant publications from the period January 1990 to September 2011. A total of ten studies on the treatment of acute Charcot osteoarthropathy with bisphosphonates were identified and included in the analysis. Only four clinical trials were published, three of which were randomised. Bisphosphonates appeared to induce significant reductions in skin temperature and bone turnover markers compared with placebo, without serious adverse events. Nevertheless, bisphosphonates did not shorten the immobilisation time. Moreover, no data were available regarding their long-term effects. Bisphosphonates have been shown to be effective for reducing bone turnover markers and skin temperature in some studies. Nevertheless, the long-term efficacy, specifically that regarding the occurrence of deformities and ulcerations, remains to be demonstrated as no follow-up studies have been published. Moreover, some studies have suggested that bisphosphonates may lengthen the resolution phase of the disease. In our opinion, the data are too weak to support the use of bisphosphonates as a routine treatment for acute Charcot neuroarthropathy.

Erratum to: Audit of acute Charcot’s disease in the UK: the CDUK study

Unfortunately the references cited in the fourth paragraph of the Introduction were incorrect. The paragraph is printed below, with the corrected references highlighted in red. It is generally accepted that off-loading in a non-removable below-knee cast or cast-walker is an essential part of management [8, 9]. In addition, the use of pamidronate was shown in an open-label study to reduce skin temperature and bone turnover markers [12], the latter effect being subsequently confirmed in a randomised controlled trial (RCT) [13]. Another small RCT demonstrated that weekly treatment with alendronate also led to a significant reduction in bone turnover markers, associated with reduced discomfort [14]. Despite these observations, the long-term clinical benefit of non-removable off-loading or bisphosphonate therapy has not yet been clearly established. Diabetologia (2012) 55:862 DOI 10.1007/s00125-011-2420-1

Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.

Five-year follow-up of a woman with pregnancy and lactation-associated osteoporosis and vertebral fractures

We report the 5-year follow-up of a young woman who developed vertebral fractures after pregnancy and lactation and was treated with active vitamin D hormone. A 32-year-old Japanese woman consulted us because of acute lower back pain caused by L2 and L5 vertebral fractures after pregnancy and lactation. Following cessation of breast-feeding, analgesia, bed rest, and wearing of a hard brace, her lower back pain disappeared within 2 months. After 5 years of treatment with alfacalcidol 1 μg daily, the lumbar spine (L1, L3, L4) bone mineral density increased by 21.4% following vigorous reductions in bone turnover markers. No osteoporotic fractures occurred, and the vertebral fractures healed. The patient experienced no side effects, including hypercalcemia. Thus, the present case report shows long-term changes in bone turnover markers and lumbar spine bone mineral density, as well as long-term safety of alfacalcidol treatment in a young woman with pregnancy and lactation-associated osteoporosis and vertebral fractures.

P4-16-05: A Randomized Phase 2 Study of a Loading Dose of Ibandronate in Patients with Bone Metastases from Breast Cancer.

Abstract Bisphosphonates have proven efficacy in reducing skeletal complications in metastatic breast cancer. Potent third generation bisphosphonates are more effective but the dose limiting toxicity is usually renal. Ibandronate is a 3rd generation bisphosphonate available in oral and intravenous form which offers many clinical advantages in ease of administration and lack of renal toxicity. A dose-response effect has been observed between 2mg and 6 mg IV doses and there is a single study suggesting that higher dosing (4 mg IV daily for 3 days) is tolerable and effective. A steady state of oral ibandronate is achieved at 8 days with oral administration but time to response is not known. In trials so far, IV ibandronate 6mgs appears safe. Due to lack of renal toxicity there is potential for further escalation of IV ibandronate. The objective of this study was to establish if an IV loading dose can improve efficacy and time to biochemical response compared to oral standard therapy and to assess the safety of a higher IV dose of ibandronate. Methods and Patients: This was an open randomised phase II study conducted on patients with bone metastases from breast cancer comparing IV ibandronate 12 mg on day 1 followed by oral ibandronate 50 mgs daily (Arm A) with standard oral therapy of 50 mgs daily from day 1 (Arm B). The primary study end-point was the percentage reduction in serum CTX from baseline by day 5 on study, secondary end- points were the percentage reduction of bone turnover markers including serum CTX from baseline end of week 8 and percentage reduction in urine NTX from baseline to day 5 on study and baseline to end of week 1–8. Bone pain was recorded by Brief Pain Inventory. Patients had metastatic breast cancer with proven bone metastases, no previous treatment with bisphosphonates or other bone directed therapy within 6 months and no change in systemic therapy within a 3 months preceding trial therapy. Sample size of 22 patients in each arm was calculated to give a 90% chance detecting a 20% difference in average percentage reduction between the IV and oral arms. Results: Seventeen patients were randomised to each study arm. A more rapid change in bone turnover markers was demonstrated in patients recieving the 12 mg loading dose of ibandronate. There was a 15.8% greater reduction of serum CTX in Arm A compared with Arm B at day 5, p=0.005. The percentage reduction of serum PINP at day 5 was also greater in Arm A, p=0.002. Over the 8 week period of study there was no overall significant difference in bone turnover markers. All patients had pain at study entry, median baseline pain severity scores were 3 in study arm and 4 in controls. Average bone pair score remained higher in treatment arm B at the end of 8 weeks. There were no additional adverse side-effects following administration of 12 mg of IV ibandronate and no evidence of additional renal toxicity. Conclusion: A 12 mg dose of IV ibandronate can be safely administered without additional renal toxicity. A rapid reduction in bone turnover markers is demonstrated within 5 days of IV loading dose of ibandronate. Potential exists for dose escalation of ibandronate. The clinical benefit of a more rapid reduction in bone turnover markers is unknown. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-05.

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. © 2012 American Society for Bone and Mineral Research

Preventing Fractures in Diabetic Dialysis Patients

Dear Editor, Skeletal health is a concern for patients with type 2 diabetes mellitus. There is an increased risk of fracture associated with diabetes (1) and some of the medications (e.g., thiazolidinediones) used to treat the diabetes (2). Chronic kidney disease (CKD), which may occur as a complication of diabetes or independently, is also a risk factor for fracture (3). The mechanisms linking diabetes, thiazolidinediones, and CKD with fractures are complex and not fully understood; however, the clinical challenges associated with the management of these disorders are ever-present and in need of solutions (4). O Saito et al. addressed one aspect of this conundrum in a study of the skeletal effects of raloxifene in a small study (N = 60) of postmenopausal Japanese women on maintenance hemodialysis (5). Study subjects were in two groups, with and without type 2 diabetes; women in each group were randomized into subgroups receiving raloxifene 60 mg daily or no raloxifene for one year. The aim of the study was to compare changes in bone turnover markers and speed of sound (SOS) measured by heel quantitative ultrasound (QUS) in subjects receiving or not receiving raloxifene. In women with postmenopausal osteoporosis, a decrease in bone turnover markers with antiresorptive therapy (i.e. raloxifene) is associated with improvement in BMD and a reduction in fracture risk. SOS, which can be used to estimate bone mineral density and T-score, is directly correlated with bone strength and fracture risk when measured by validated QUS instruments. At the end of one year in the Saito et al. study, the diabetics receiving raloxifene had a significantly higher SOS than the control diabetics (P = 0.02), but otherwise there were no significant differences in SOS or bone turnover markers. Comparing the change from baseline values between the subgroups, it was found that SOS increased and serum N-telopeptide (NTX) decreased in diabetics and non-diabetics receiving raloxifene compared with the control subgroups (P < 0.05). The findings of this study suggest the possibility that raloxifene may have beneficial skeletal effects in postmenopausal women on hemodialysis. However, this is a hypothesis that requires further study before raloxifene can be recommended for clinical use in these patients. At this time, there are more questions than answers. In patients with end-stage CKD, it is not clear whether a reduction in bone turnover markers or an increase SOS with treatment is associated with a reduction in fracture risk. Since some postmenopausal women with end-stage CKD could have CKD-mineral and bone disorder with low bone turnover, an antiresorptive medication may not be appropriate for all. There are safety concerns with the use of raloxifene, a drug associated with increased risk of thromboembolic events, in patients with end-stage CKD and/or diabetes mellitus, since these patients are at high baseline risk for cardiovascular disease. More data are needed to better define the bone disease in patients with end-stage CKD, with or without diabetes, and determine whether pharmacological interventions can reduce fracture risk with a favorable balance of benefit and risk.

Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys

Denosumab is a fully human monoclonal antibody that inhibits RANKL, a protein essential for osteoclast formation, function, and survival. Osteoclast inhibition with denosumab decreased bone resorption, increased bone mineral density (BMD), and reduced fracture risk in osteoporotic women. The effects of 16months of continuous osteoclast inhibition on bone strength parameters were examined in adult ovariectomized (OVX) cynomolgus monkeys (cynos). One month after surgery, OVX cynos (n=14-20/group) were treated monthly with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg). Sham-operated controls were treated with vehicle (n=17). OVX-Veh exhibited early and persistent increases in the resorption marker CTx, followed by similar increases in the formation marker BSAP, consistent with increased bone remodeling. Denosumab reduced CTx and BSAP throughout the study to levels significantly lower than in OVX-Veh or Sham-Veh, consistent with reduced remodeling. Increased remodeling in OVX-Veh led to absolute declines in areal BMD of 4.3-7.4% at the lumbar spine, total hip, femur neck, and distal radius (all p<0.05 vs baseline). Denosumab significantly increased aBMD at each site to levels exceeding baseline or OVX-Veh controls, and denosumab significantly increased cortical vBMC of the central radius and tibia by 7% and 14% (respectively) relative to OVX-Veh. Destructive biomechanical testing revealed that both doses of denosumab were associated with significantly greater peak load for femur neck (+19-34%), L3-L4 vertebral bodies (+54-55%), and L5-L6 cancellous cores (+69-82%) compared with OVX-Veh. Direct assessment of bone tissue material properties at cortical sites revealed no significant changes with denosumab. For all sites analyzed biomechanically, bone mass (BMC) and strength (load) exhibited strong linear correlations (r(2)=0.59-0.85 for all groups combined). Denosumab did not alter slopes of load-BMC regressions at any site, and denosumab groups exhibited similar or greater load values at given BMC values compared with OVX-Veh or Sham. In summary, denosumab markedly reduced biochemical markers of bone remodeling and increased cortical and trabecular bone mass in adult OVX cynos. Denosumab improved structural bone strength parameters at all sites analyzed, and strength remained highly correlated with bone mass. There was no evidence for reduced material strength properties of cortical bone with denosumab over this time period, which approximates to 4years of remodeling in the slower-remodeling adult human skeleton. These data indicate that denosumab increased bone strength by increasing bone mass and preserving bone quality.

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study

This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39). Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

Increased osteocyte death and mineralization inside bone after parathyroidectomy in patients with secondary hyperparathyroidism

In order to gain insight into the mechanisms underlying the dynamic changes in bone metabolism and bone quality after parathyroidectomy (PTX) in secondary hyperparathyroid patients with high levels of parathyroid hormone (PTH), we performed bone histomorphometric analysis with tetracycline labeling in iliac bone biopsy specimens taken before and after PTX, with special attention paid to osteocytes. At 2 to 4 weeks after PTX, PTH concentrations decreased markedly with evident reductions in bone turnover markers. Histomorphometry revealed that at 2 to 4 weeks following PTX, the osteoclast surface decreased to nearly 0%, with a substantial increase in osteoid volume and a reduction in fibrosis volume. Labeling with tetracycline was observed not only at the mineralization front on the bone surface but also around the osteocyte lacunar walls and canaliculi within both the basic multicellular units (BMUs) and bone structural units (BSUs), suggesting that mineralization was taking place along the lacunocanalicular system after PTX. The tetracycline-labeled area was much greater in the BSUs than in the BMUs and at the mineralization front, and the tetracycline labeling in the BSUs was markedly increased after PTX compared with that in the low- and high-PTH control groups without PTX. The osteocyte number was decreased significantly after PTX, concomitant with an increase in the number of empty lacunae and a reduction of lacunar volume. Thus the increased osteocyte death and mineralization around the lacunocanalicular system in association with a rapid decline in PTH may underlie the changes in bone metabolism and quality that occur following PTX.

Response to Oral Bisphosphonates in Subgroups of Younger and Older Postmenopausal Women

Although the effects of bisphosphonates in bone are known for postmenopausal women, it is not known if younger postmenopausal women have a similar response. Furthermore, it is not known if the effects of alendronate and risedronate differ in postmenopausal women in regard to age, specifically in women at or younger than the mean age of natural menopause. Our aim was to examine the effects of two oral bisphosphonates in postmenopausal women by age. This was a post-hoc analysis of postmenopausal women <55 or > or =55 years old with low bone mineral density (BMD), randomized to once weekly alendronate 70 mg or risedronate 35 mg for 1 year with 1-year extensions in U.S. and International Fosamax Actonel Comparison Trials. In both age subgroups of postmenopausal women, alendronate produced significantly greater mean BMD increases from baseline than risedronate at hip trochanter, lumbar spine, total hip, and femoral neck. Changes in BMD were not significantly different between younger and older alendronate-treated women, although treatment differences favoring alendronate were numerically greater for younger than older postmenopausal women at all sites. Significantly greater reductions in bone turnover markers also occurred with alendronate vs. risedronate in both subgroups. Tolerability was similar between treatments. In this post-hoc subgroup analysis of older and younger postmenopausal women receiving alendronate or risedronate, larger treatment differences in BMD gain in younger compared with older women suggest that patient age may affect the relative efficacy of these antiresorptive drugs.

Denosumab – an emerging treatment for postmenopausal osteoporosis

Importance of the field: Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling. Denosumab is an investigational fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL), a cytokine member of the TNF family that is the principal mediator of osteoclastic bone resorption.Areas covered in this review: The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009.What the reader will gain: This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis.Take home message: In postmenopausal women with osteoporosis, denosumab (60 mg by subcutaneous injection every 6 months) increased bone mineral density, reduced bone turnover markers, and reduced the risk of vertebral, hip and non-vertebral fractures. Denosumab was well tolerated with a safety profile generally similar to placebo. It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis.

Zoledronic Acid for the Prevention of Bone Loss in Postmenopausal Women With Low Bone Mass

To evaluate the efficacy of zoledronic acid in the prevention of bone loss in postmenopausal women with low bone mass. In this 2-year, randomized, multicenter, double-blind, placebo-controlled study, postmenopausal women with low bone mass were selected randomly to receive either zoledronic acid 5 mg intravenously at randomization and at month 12 (zoledronic acid 2 x 5 mg), zoledronic acid 5 mg intravenously only at randomization and placebo at month 12 (zoledronic acid 1 x 5 mg), or placebo at randomization and at month 12 (placebo). The primary efficacy endpoint was the percentage change in lumbar spine bone mineral density (BMD) (lumbar spine BMD) at month 24 relative to baseline. Both zoledronic acid 2 x 5 mg and zoledronic acid 1 x 5 mg regimens significantly increased mean lumbar spine BMD compared with placebo at month 24 (5.18% and 4.42% compared with -1.32%, respectively, both P<.001). Similarly, significantly greater increases for both zoledronic acid regimens relative to placebo were observed for lumbar spine BMD at month 12 and for BMD at the proximal femur sites (total hip, femoral neck, trochanter) at month 12 and 24 (all P<.001). Both zoledronic acid regimens significantly reduced bone turnover markers over time relative to placebo (all P<.001), although changes with zoledronic acid 2 x 5 mg regimen were sustained greater during the second year relative to zoledronic acid 1 x 5 mg. The overall incidence of adverse events and serious adverse events were similar across all treatment groups. Both once-yearly dosing and a single dose of intravenous zoledronic acid 5 mg prevented bone loss for 2 years and were well-tolerated in postmenopausal women with low bone mass. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00132808. I.

Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis.

Lasofoxifene is a selective estrogen receptor modulator (estrogen agonist/antagonist) that has completed phase III trials to evaluate safety and efficacy for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy in postmenopausal women. In postmenopausal women with low or normal bone mineral density (BMD), lasofoxifene increased BMD at the lumbar spine and hip and reduced bone turnover markers compared with placebo. In women with postmenopausal osteoporosis, lasofoxifene increased BMD, reduced bone turnover markers, reduced the risk of vertebral and nonvertebral fractures, and decreased the risk of estrogen receptor-positive breast cancer. In postmenopausal women with low bone mass, lasofoxifene improved the signs and symptoms of vulvovaginal atrophy. Clinical trials show that lasofoxifene is generally well tolerated with mild to moderate adverse events that commonly resolve even with drug continuation. Lasofoxifene has been associated with an increase in the incidence of venous thromboembolic events, hot flushes, muscle spasm, and vaginal bleeding. It is approved for the treatment of postmenopausal women at increased risk for fracture in some countries and is in the regulatory review process in others.