Beneficial effects of denosumab on muscle performance in patients with low BMD: a retrospective, propensity score-matched study.

This study examined the effects of denosumab compared to bisphosphonates and vitamin D alone on muscle performance in patients with low BMD. While grip force improved in both the denosumab and bisphosphonate group, a superior increase in chair rising test force was observed in the denosumab group. INTRODUCTION: The aim of this study was to investigate the effect of the anti-resorptive agent denosumab (Dmab) on upper and lower limb muscle performance compared to bisphosphonate (BP) treatment and vitamin D supplementation alone (i.e., basic therapy) in patients with low BMD. METHODS: This retrospective, propensity score-matched (sex, age, BMI, follow-up time) cohort study included 150 osteopenic or osteoporotic patients receiving basic (n = 60), BP (n = 30) or Dmab (n = 60) therapy. All patients underwent a musculoskeletal assessment at baseline and follow-up, including DXA, laboratory bone metabolism parameters, grip force, and chair rising test mechanography. Mean annual percentage changes were calculated and compared between study groups. RESULTS: After a mean follow-up period of 17.6 ± 9.0 months, a significantly higher increase in grip force in both the Dmab (p < 0.001) and BP group (p = 0.001) compared to the vitamin D group was observed (vitamin D = - 6.1 ± 10.2%; BP = + 0.8 ± 8.2%; Dmab = + 5.1 ± 25.5%). The Dmab group showed a significantly higher increase in chair rising test force compared to the BP group (vitamin D = + 5.8 ± 12.7%; BP = + 0.9 ± 8.6%; Dmab = + 8.2 ± 14.4%; Dmab vs. BP p = 0.03). Neither the changes in BMD nor in bone metabolic parameters were associated with changes in muscle performance. CONCLUSION: Dmab resulted in increased muscle strength in the upper and lower limbs, indicating systemic rather than site-specific effects as compared to BP. Based on these findings, Dmab might be favored over other osteoporosis treatments in patients with low BMD and poor muscle strength.

Therapeutic Options for the Management of Aromatase Inhibitor- Associated Bone Loss.

BACKGROUND: Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy. Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease- free survival and overall survival; it involves several endocrine treatment regimens, including Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women. OBJECTIVES: The objective of this review is to evaluate the therapeutic options in the management of Aromatase Inhibitor-Associated Bone Loss (AIBL). METHODS: We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL. RESULTS: Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease- free survival. CONCLUSIONS: AI, that are the pillar of the systemic treatment for patients with hormone receptorpositive breast cancer, are associated with different side effects, and in particular, osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.

Denosumab vs. zoledronic acid treatment in post-menopausal breast cancer: a 2-year prospective observational study.

Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm2) and total hip (0.019 g/cm2) in the denosumab group but no change at the femoral neck(-0.011g/cm2). In the ZA group, we observed no significant change at the spine (0.015 g/cm2) and total hip (-0.001g/cm2) and a small significant decrease at the femoral neck (-0.037 g/cm2). However, when we compared BMD change between the treatment groups, we found no significant difference.Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA.Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis.We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years.We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.

The effect of denosumab in breast cancer patients receiving adjuvant aromatase inhibitors: 36-month results.

INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

Real-life use of denosumab 120 mg every 12 weeks in prolonged treatment over 2 years of patients with breast cancer bone metastases.

PURPOSE: To analyze the activity and safety of denosumab (DNS) 120 mg every 3 months over 2 years of standard treatment (120 mg SC every 4 weeks) of patients with breast cancer bone metastases in real life. METHODS: We prospectively analyzed the activity and safety of denosumab 120 mg every 3 months and 120 mg every 4 weeks in the treatment of 22 patients with breast cancer bone metastases over 2 years of standard treatment. All patients received specific concomitant antineoplastic treatment, chemotherapy or endocrine therapy and/or target therapy. Oral daily calcium (≥500 mg) and vitamin D (≥1000 U) supplement was recommended. RESULTS: Of the 22 patients treated with denosumab, 4 (18.1%) had at least 1 skeletal related event (SRE); 3 (13.6%) had 1 SRE and 1 patient (4.5%) had 2 SRE, all 10% treated with radiotherapy. Overall, no denosumab-related G3 adverse events occurred; in particular, no cases of osteonecrosis of the jaw have been recorded. The decrease in serum calcium levels was mild (G1, 2 patients, 9%), and recovered in a short time (within 2 weeks) with an increase in the oral support of calcium and vitamin D. CONCLUSIONS: Denosumab confirms a good activity profile in terms of delaying and preventing SREs in breast cancer patients and a good safety profile. It represents an optimal treatment resource which doesn't necessitate renal function monitoring and has the convenience of a subcutaneous administration.

Efficacy of denosumab co-administered with vitamin D and Ca by baseline vitamin D status.

INTRODUCTION: In anti-osteoporosis drug trials, vitamin D and calcium (Ca) are common supplements; however, the optimal dose of each is unclear. Using data from the randomized, double-blind, placebo-controlled DIRECT trial, we assessed whether baseline serum 25-hydroxy vitamin D (25[OH]D) level influences the efficacy of denosumab co-administered with vitamin D and Ca. MATERIALS AND METHODS: In this prespecified sub-analysis, subjects with primary osteoporosis who received denosumab or placebo, plus vitamin D (≥ 400 IU/day) and Ca (≥ 600 mg/day), were classified as 25(OH)D deficient (< 20 ng/mL), insufficient (≥ 20 to < 30 ng/mL), and sufficient (≥ 30 ng/mL). Study endpoints included absolute serum 25(OH)D level at baseline, 12 months, and 24 months; change in serum 25(OH)D and bone mineral density (BMD) status from baseline; and incidence of new vertebral fractures at 24 months. RESULTS: In 475 denosumab-treated and 481 placebo-treated subjects, proportions with deficient/insufficient/sufficient 25(OH)D at baseline were 53.1%/37.1%/9.9% and 50.9%/42.0%/7.1%, respectively. Supplementation significantly increased mean serum 25(OH)D levels; at 24 months, mean levels were > 30 ng/mL (sufficient) in both treatment groups. Increase in BMD over time was higher in the denosumab group vs. placebo group in all three vitamin D status groups. At month 24, denosumab-treated subjects with deficient/insufficient baseline 25(OH)D had a significantly lower risk of new vertebral fracture vs. placebo-treated subjects. CONCLUSION: Among DIRECT trial subjects supplemented with ≥ 400 IU/day of vitamin D and ≥ 600 mg/day of Ca, baseline 25(OH)D sufficiency may not influence the efficacy of denosumab in increasing BMD or preventing vertebral fractures.

Predictive factors for the efficacy of denosumab in postmenopausal Japanese women with non-metastatic breast cancer receiving adjuvant aromatase inhibitors: a combined analysis of two prospective clinical trials.

Aromatase inhibitors (AIs) are the gold standard therapy for breast cancer in postmenopausal women. AI suppresses the conversion of androgens to estrogens; however, this results in osteopenia, osteoporosis, and bone fracture, thus reducing the patient's quality of life. The use of adjuvant denosumab reduces the risk of clinical fractures in postmenopausal patients with breast cancer receiving AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. In this study, we aimed to investigate the predictive factors for the efficacy of denosumab in postmenopausal patients with breast cancer treated with AI by analyzing the results of two prospective trials. The patients received 60 mg denosumab subcutaneously every 6 months. The primary endpoint was percentage change in lumbar spine bone mineral density (BMD) from baseline to month 12 in lumbar spine. Post hoc analysis and T tests were performed. A total of 205 patients were enrolled. At 12 and 24 months, the lumbar spine BMD increased by 5.6% [95% confidence interval (CI) 4.9-6.3] and 8.3% (95% CI 7.5-9.1), respectively. Subgroup analysis was conducted according to the time of AI therapy initiation, type of AI therapy, age, time since menopause, baseline body mass index, and BMD. The results showed that baseline lumbar and left femoral BMD was significantly associated with a percentage change in these sites, respectively. In addition, baseline left femoral BMD was also associated with a change in lumbar BMD. In conclusion, the baseline BMD in the lumbar spine was a predictive indicator for the efficacy of denosumab in this site and the baseline BMD in left femoral neck was a predictive indicator in lumbar spine and left femur.

Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial.

Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.

Effects of denosumab on bone mineral density in Japanese women with osteoporosis treated with aromatase inhibitors for breast cancer.

Adjuvant aromatase inhibitor (AI) therapy, for hormone receptor-positive breast cancer, in postmenopausal women is associated with bone loss, leading to an increased risk of fractures. Denosumab, an antibody raised against the receptor activator of nuclear factor-κB ligand, has been proven to protect against AI-induced bone loss. Hence, we aimed to determine whether denosumab is effective in postmenopausal Japanese women with osteoporosis, treated with AI. We prospectively evaluated the bone mineral density (BMD) in the lumbar spine and the bilateral femoral neck in 102 postmenopausal women with clinical hormone receptor-positive breast cancer, stages I-IIIA, during a postoperative period of 12 months. The other inclusion criteria for this study were: women that should receive AIs as adjuvant therapy and those with evidence of osteoporosis (lumbar spine or bilateral femoral neck BMD, equivalent to T-score classification of ≤ - 2.5) upon enrollment. The patients received supplemental calcium, vitamin D, and 60 mg of subcutaneous denosumab every 6 months. The BMD of the lumber spine increased by 4.9 and 6.6% at 6 and 12 months, respectively. An increase in BMD was observed at the femoral neck, bilaterally. Hypocalcemia ≥ grade 2, osteonecrosis of the jaw, and non-traumatic clinical fracture were not observed in this study. Our findings revealed that biannual treatment with denosumab is associated with a great increase of BMD in Japanese women receiving adjuvant AI therapy, irrespective of their previous history of AI therapy.

Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.

BACKGROUND: Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. METHODS: This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. RESULTS: At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. CONCLUSIONS: Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

[ASBMR topics from clinical research(osteoporosis and sarcopenia).]

There are a lot of progressive topics about osteoporosis and sarcopenia in 2018 ASBMR Annual Meeting, involving an association between diabetes and bone microarchitecture, associations between atypical femoral fractures and bisphosphonate drug holidays as well as pre-treatment bone mineral density, an effect of combined denosumab and high-dose teriparatide on bone parameters, and relationships between muscle and deuterated creatine, a selective androgen receptor modulator, and high-dose vitamin D supplementation.

Denosumab: Prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures.

Denosumab, a bone-modifying agent, reduces the risk of skeletal-related events in patients with bone metastases from solid tumors and is generally well tolerated. However, hypocalcemia, osteonecrosis of the jaw (ONJ) and atypical fracture are potential and important toxicities of denosumab therapy that require attention. In pivotal phase III trials in patients with bone metastases from solid tumors, the incidence of hypocalcemia was 9.6% in denosumab-treated patients, with most events being asymptomatic, grade 2 and resolving by week 4. Established hypocalcaemia requires additional short-term calcium and vitamin D supplementation and, if severe, administration of intravenous calcium. ONJ was reported in 1.8% of patients receiving denosumab over 3 years in these trials. Involvement of an experienced oro-maxillary surgeon is important if ONJ is suspected. Atypical fractures were rare in a large study of denosumab using the dose and scheduling approved for the treatment of osteoporosis. To prevent toxicities, patients should maintain calcium and vitamin D supplementation, good oral hygiene and regular dental reviews throughout treatment. This article presents case studies from our clinical practice and discusses the pathophysiology of these toxicities along with guidance on prevention, diagnosis and management.

Updates on the role of receptor activator of nuclear factor κB/receptor activator of nuclear factor κB ligand/osteoprotegerin pathway in breast cancer risk and treatment.

PURPOSE OF REVIEW: Treatment with bisphosphonates and denosumab is the standard of care in bone metastatic disease. In addition, the adjuvant therapy of denosumab or bisphosphonates is very effective to prevent loss of bone mineral density, for example in osteoporosis. However, it is still unclear if this therapy has an influence on preventing cancer. RECENT FINDINGS: Since the identification of novel genes in the 1980s, it took about 30 years until denosumab, as a fully human mAb against receptor activator of nuclear factor (NF)-κB ligand (RANKL), could be introduced to clinical practice. The discovery of the receptor activator of NF-κB/RANKL/osteoprotegerin pathway in the 1990s is an example of how modern databases of genes were utilized to discover new pathways relevant to a variety of diseases. The essential role of this pathway for the function, differentiation and survival of osteoclasts, and the influence on the bone microenvironment helped to understand the vicious circle of bone resorption and destruction in many skeletal diseases. SUMMARY: In the following review, we discuss the important role of rational targeting concerning receptor activator of NF-κB/RANKL/osteoprotegerin and the bisphosphonate therapy and provide an update for the related treatment of patients suffering from breast cancer and further implications for clinical practice and research using denosumab as a potential chemoprevention in BRCA1-related breast cancer.