Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports.

BACKGROUND: As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements. CASE REPORT: We report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases. Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine. CONCLUSIONS: We observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Sustained hypophosphatemia after denosumab in a patient on hemodialysis.

An 81-year-old Caucasian man who had commenced thrice weekly hemodialysis (HD) three months earlier, presented with a hip fracture, two vertebral fractures and a bone mineral density T-score of -3.6. He had received weekly iron sucrose infusions for 6 weeks and alphacalcidol on dialysis days. Although he suffered from coeliac disease and cirrhosis, he was fully ambulatory and well-nourished. He was normocalcaemic with a marginally low plasma phosphate and the PTH was 11.8 pmol/L (<2-times the upper range of the assay). In view of his severe osteoporosis, it was decided to treat him with denosumab (dmab). Laboratory assessment 2 weeks post dmab showed severe hypophosphatemia and hypocalcemia; phosphate 0.11 mmol/L and ionized calcium 0.83 mmol/L, and he was admitted for intravenous phosphate infusion. Three months later he remained on a phosphate supplement. The case illustrates that, in addition to the risks of hypocalcemia in patients with kidney failure and high bone turnover, kidney failure patients without evidence of high bone turnover, can also be at risk of hypocalcemia and severe hypophosphatemia requiring acute hospitalization and phosphate infusion. The potential role of compromised phosphate absorption versus increased deposition will be discussed. We recommend a cautious approach to dmab therapy in patients on dialysis, with evaluation of bone turnover and serum phosphate levels prior to initiation of treatment.

Fat Body Mass and Vertebral Fracture Progression in Women With Breast Cancer.

Importance: Women with early breast cancer (EBC) exposed to aromatase inhibitors (AIs) may experience fragility fractures despite treatment with bone-active drugs. Risk factors for fractures in patients receiving AIs and denosumab have not been explored to date. Objectives: To evaluate whether an association exists between dual x-ray absorptiometry (DXA)-measured fat body mass (FBM) and vertebral fracture (VF) progression in postmenopausal women with EBC undergoing adjuvant therapy with AIs in combination with denosumab and to examine whether VF was associated with common risk factors for bone fracture and parameters of body composition other than FBM. Design, Setting, and Participants: For this prospective, single-center, cohort study, 237 patients with EBC who were undergoing adjuvant treatment with AIs and denosumab (60 mg every 6 months) were enrolled at the Breast Unit of the ASST Spedali Civili of Brescia from September 2014 to June 2018. Data analysis was conducted in June 2022. Exposure: Body composition parameters, bone mineral density, and morphometric VFs were assessed by DXA at study entry and after 18 months of therapy. Main Outcomes and Measures: VF progression, defined as either new or worsening of preexisting VFs, between the 2 time points. Results: Of the 237 patients enrolled (median [range] age, 61 [28-84] years), 17 (4.4%) reported VF progression. Univariable analysis found an association between VF progression and a history of clinical fractures (odds ratio [OR], 3.22; 95% CI, 1.19-8.74; P = .02), Fracture Risk Assessment Tool (FRAX) score for major fractures (OR, 4.42; 95% CI, 1.23-13.79; P = .04), percentage of FBM (OR, 6.04; 95% CI, 1.69-21.63; P = .006), and android fat (OR, 9.58; 95% CI, 1.17-78.21; P = .04) and an inverse association with appendicular lean mass index-FBM ratio (OR, 0.25, 95% CI, 0.08-0.82; P = .02). Multivariable analysis revealed percentage of FBM (OR, 5.41; 95% CI, 1.49-19.59; P = .01) and FRAX score (OR, 3.95; 95% CI, 1.09-14.39; P = .04) as independent variables associated with VF progression. Conclusions and Relevance: The findings of this study suggest that baseline FBM is an independent factor for VF progression in patients with EBC treated with adjuvant AIs and denosumab. This observation is new and indicates that diet and exercise may synergize with denosumab in the management of bone health in this patient setting.

Efficacy and safety of denosumab treatment for Korean patients with Stage 3b-4 chronic kidney disease and osteoporosis.

BACKGROUND/AIMS: We evaluated the efficacy and safety of denosumab treatment in severe chronic kidney disease (CKD) patients with osteoporosis. We also investigated whether the treatment affects the coronary artery calcifications. METHODS: Twenty-seven postmenopausal women with Stage 3b-4 CKD and osteoporosis were enrolled. Twenty patients received denosumab plus calcium carbonate and vitamin D, and seven controls received calcium carbonate and vitamin D for 1 year. Dual-energy X-ray absorptiometry and coronary artery calcium (CAC) scoring computed tomography were performed before and after treatment. Hypocalcemic symptoms and serum calcium levels were evaluated. RESULTS: After 1 year of treatment, the percent changes of femur neck (3.6 ± 3.2% vs. -0.7 ± 4.4%, p = 0.033) and total hip (3.4 ± 3.8% vs. -1.9 ± 2.1%, p = 0.001) bone mineral density (BMD) were significantly increased in the denosumab treated group compared to the control group. However, the percent change of lumbar spine BMD did not differ between two groups (5.6 ± 5.9% vs. 2.7 ± 3.9%, p = 0.273). The percent change of bone alkaline phosphatase was significantly different in the denosumab-treated group and control group (-31.1 ± 30.0% vs. 0.5 ± 32.0%, p = 0.027). CAC scores did not differ between groups. No hypocalcemic events occurred in both groups. CONCLUSION: If carefully monitored and supplemented with calcium and vitamin D, denosumab treatment for 1 year provides significant benefits in patients with Stage 3b-4 CKD and osteoporosis. However, denosumab treatment did not affect coronary artery calcifications in these patients.

The role of bone modifying agents for secondary osteoporosis prevention and pain control in post-menopausal osteopenic breast cancer patients undergoing adjuvant aromatase inhibitors.

Introduction: Hormonal therapy (HT) blocks the hormone-mediated growth signal dramatically reducing estrogenic levels with aromatase inhibitors (AIs) becoming a crucial component of the treatment mainstay in patients with early breast cancer (BC). Postmenopausal BC patients receiving HT present with a significant risk of secondary osteoporosis with AIs further reducing estrogen levels and ultimately leading to an accelerated rate of bone resorption and thus decreased bone mineral density (BMD). This was an observational retrospective clinical study that consecutively enrolled early BC patients with osteopenia to compare the impact of alendronate versus denosumab on secondary osteoporosis prevention and pain control. Methods: We identified two groups of patients treated with denosumab 60 mg by subcutaneous injection once every six months or alendronate 70 mg orally once a week. All the patients underwent a baseline physiatric evaluation (T0) and underwent a follow-up visit after 18 months (T1) together with femoral and vertebral Dual-Energy X-ray Absorptiometry (DEXA) exam evaluating T-Score marks. From September 2015 to December 2019 a total of 50 early (stage I-III) BC patients were considered eligible and consecutively enrolled in our study if they met pre-specified inclusion criteria. Results: In the entire observed population, the addition of treatment with alendronate or denosumab led to a significant T-score improvement at the lumbar spine level (-1.92 vs -1.52, p=0.03), with a comparable contribution from alendronate (-1.60 vs -1.45, p=0.07) and denosumab (-2.26 vs -1.58, p=0.07). Regarding the femoral region, neither alendronate (-0.98 vs -1.07, p=0.23) nor denosumab (-1.39 vs -1.34, p=0.81) were able to produce any statistically relevant effect. However, concerning pain control, BMAs had a significant impact on reducing NRS scoresin the general population (T1 3.94 vs. baseline 4.32, p=0.007), with a likelyspecific contribution from alendronate (T1 3.52 vs. baseline 3.88, p=0.004) compared to denosumab (T1 4.36 vs baseline 4.76, p=0.12), without any differences in analgesic therapy assumption over time (p=0.93). Discussion: Both alendronate and denosumab significantly contributed to preventing secondary osteoporosis in early BC patients with low BMD undergoing AIs, mostly at the lumbar spine level. Moreover, alendronate seemed to significantly impact pain control in such patients further supporting alendronate as a cost-effective option in this frail setting, although BMAs particularities should be carefully considered on an individual basis according to specific clinical contexts.

Treatment for osteoporosis in people with beta-thalassaemia.

BACKGROUND: Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with beta-thalassaemia, osteoporosis represents an important cause of morbidity and is due to a number of factors. First, ineffective erythropoiesis causes bone marrow expansion, leading to reduced trabecular bone tissue with cortical thinning. Second, excessive iron loading causes endocrine dysfunction, leading to increased bone turnover. Lastly, disease complications can result in physical inactivity, with a subsequent reduction in optimal bone mineralization. Treatments for osteoporosis in people with beta-thalassaemia include bisphosphonates (e.g. clodronate, pamidronate, alendronate; with or without hormone replacement therapy (HRT)), calcitonin, calcium, zinc supplementation, hydroxyurea, and HRT alone (for preventing hypogonadism). Denosumab, a fully human monoclonal antibody, inhibits bone resorption and increases bone mineral density (BMD). Finally, strontium ranelate simultaneously promotes bone formation and inhibits bone resorption, thus contributing to a net gain in BMD, increased bone strength, and reduced fracture risk. This is an update of a previously published Cochrane Review. OBJECTIVES: To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which includes references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of most recent search: 4 August 2022. SELECTION CRITERIA: Randomized controlled trials (RCTs) in people with beta-thalassaemia with: a BMD Z score below -2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and premenopausal females aged over 15 years; or a BMD T score below -2.5 SDs for postmenopausal females and males aged over 50 years. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and risk of bias of the included RCTs, and extracted and analysed data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included six RCTs (298 participants). Active interventions included bisphosphonates (3 trials, 169 participants), zinc supplementation (1 trial, 42 participants), denosumab (1 trial, 63 participants), and strontium ranelate (1 trial, 24 participants). The certainty of the evidence ranged from moderate to very low and was downgraded mainly due to concerns surrounding imprecision (low participant numbers), but also risk of bias issues related to randomization, allocation concealment, and blinding. Bisphosphonates versus placebo or no treatment Two RCTs compared bisphosphonates to placebo or no treatment. After two years, one trial (25 participants) found that alendronate and clodronate may increase BMD Z score compared to placebo at the femoral neck (mean difference (MD) 0.40, 95% confidence interval (CI) 0.22 to 0.58) and the lumbar spine (MD 0.14, 95% CI 0.05 to 0.23). One trial (118 participants) reported that neridronate compared to no treatment may increase BMD at the lumbar spine and total hip at six and 12 months; for the femoral neck, the study found increased BMD in the neridronate group at 12 months only. All results were of very low-certainty. There were no major adverse effects of treatment. Participants in the neridronate group reported less back pain; we considered this representative of improved quality of life (QoL), though the certainty of the evidence was very low. One participant in the neridronate trial (116 participants) sustained multiple fractures as a result of a traffic accident. No trials reported BMD at the wrist or mobility. Different doses of bisphosphonate compared One 12-month trial (26 participants) assessed different doses of pamidronate (60 mg versus 30 mg) and found a difference in BMD Z score favouring the 60 mg dose at the lumbar spine (MD 0.43, 95% CI 0.10 to 0.76) and forearm (MD 0.87, 95% CI 0.23 to 1.51), but no difference at the femoral neck (very low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment. Zinc versus placebo One trial (42 participants) showed zinc supplementation probably increased BMD Z score compared to placebo at the lumbar spine after 12 months (MD 0.15, 95% CI 0.10 to 0.20; 37 participants) and 18 months (MD 0.34, 95% CI 0.28 to 0.40; 32 participants); the same was true for BMD at the hip after 12 months (MD 0.15, 95% CI 0.11 to 0.19; 37 participants) and 18 months (MD 0.26, 95% CI 0.21 to 0.31; 32 participants). The evidence for these results was of moderate certainty. The trial did not report BMD at the wrist, fracture incidence, mobility, QoL, or adverse effects of treatment. Denosumab versus placebo Based on one trial (63 participants), we are unsure about the effect of denosumab on BMD Z score at the lumbar spine, femoral neck, and wrist joint after 12 months compared to placebo (low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment, but the investigators reported a reduction in bone pain measured on a visual analogue scale in the denosumab group after 12 months of treatment compared to placebo (MD -2.40 cm, 95% CI -3.80 to -1.00). Strontium ranelate One trial (24 participants) only narratively reported an increase in BMD Z score at the lumbar spine in the intervention group and no corresponding change in the control group (very low-certainty evidence). This trial also found a reduction in back pain measured on a visual analogue scale after 24 months in the strontium ranelate group compared to the placebo group (MD -0.70 cm (95% CI -1.30 to -0.10); we considered this measure representative of improved quality of life. AUTHORS' CONCLUSIONS: Bisphosphonates may increase BMD at the femoral neck, lumbar spine, and forearm compared to placebo after two years' therapy. Zinc supplementation probably increases BMD at the lumbar spine and hip after 12 months. Denosumab may make little or no difference to BMD, and we are uncertain about the effect of strontium on BMD. We recommend further long-term RCTs on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia-associated osteoporosis.

Denosumab-induced hypocalcemia post bariatric surgery-a severe and protracted course: a case report.

BACKGROUND: Denosumab is known to cause abnormalities in calcium homeostasis. Most of such cases have been described in patients with underlying chronic kidney disease or severe vitamin D deficiency. Previous bariatric surgery could also contribute to hypocalcemia and deterioration in bone health. CASE PRESENTATION: We present a case of a 61-year-old Malay female with worsening bilateral limb weakness, paresthesia, and severe carpopedal spasm a week after receiving subcutaneous denosumab for osteoporosis. She had a history of gastric bypass surgery 20 years ago. Post gastric bypass surgery, she was advised and initiated on lifelong calcium, vitamin D, and iron supplementations that she unfortunately stopped taking 5 years after surgery. Her last serum blood tests, prior to initiation on denosumab, were conducted in a different center, and she was told that she had a low calcium level; hence, she was advised to restart her vitamin and mineral supplements. Laboratory workup revealed severe hypocalcemia (adjusted serum calcium of 1.33 mmol/L) and mild hypophosphatemia (0.65 mmol/L), with normal magnesium and renal function. Electrocardiogram showed a prolonged QTc interval. She required four bolus courses of intravenous calcium gluconate, and three courses of continuous infusions due to retractable severe hypocalcemia (total of 29 vials of 10 mL of 10% calcium gluconate intravenously). In view of her low vitamin D level of 33 nmol/L, she was initiated on a loading dose of cholecalciferol of 50,000 IU per week for 8 weeks. However, despite a loading dose of cholecalciferol, multiple bolus courses, and infusions of calcium gluconate, her serum calcium hovered around only 1.8 mmol/L. After 8 days of continuous intravenous infusions of calcium gluconate, high doses of calcitriol 1.5 µg twice daily, and 1 g calcium carbonate three times daily, her serum calcium stabilized at approximately 2.0 mmol/L. She remained on these high doses for over 2 months, before they were gradually titrated down to ensure sustainability of a safe calcium level. CONCLUSION: This case report highlights the importance of screening for risk factors for iatrogenic hypocalcemia and ensuring normal levels before initiating denosumab. The patient history of bariatric surgery could have worsened the hypocalcemia, resulting in a more severe presentation and protracted response to oral calcium and vitamin D supplementation.

Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Osteoporosis Drug Increases Hypocalcemia Risk in Dialysis Patients.

The Food and Drug Administration has issued a Drug Safety Communication regarding the osteoporosis drug denosumab (Prolia). The communication warns of an increased risk of significant hypocalcemia with denosumab use in patients with advanced kidney disease, especially if they also receive dialysis.Nurses and NPs need to assess for hypocalcemia in patients with advanced kidney disease who receive denosumab. Patient education concerning the need for calcium and vitamin D supplements and repeated laboratory monitoring is crucial.

Monoclonal antibodies for treatment of osteoporosis.

Osteoporosis is a chronic disease with high unmet medical need. It is characterized by low bone mass and deteriorated bone architecture, leading to increased risk of fragility fractures, with vertebral and hip fractures representing the highest risk of morbidity and mortality. The baseline therapeutic approach to osteoporosis treatment has been based on adequate intake of calcium and supplementation of vitamin D. In this review, we focus on two approved monoclonal antibodies, romosozumab and denosumab, which have been shown to be efficient and safe options to prevent patient fractures. Romosozumab is a humanized monoclonal antibody IgG2 isotype that extracellularly binds sclerostin with high affinity and specificity. Denosumab is a fully human monoclonal antibody IgG2 isotype that binds RANK ligand (RANKL) and prevents the interaction of RANKL with its receptor RANK. Denosumab is an antiresorptive that has been used for more than a decade, and romosozumab has recently been approved for clinical practice worldwide.

The clinical effectiveness of denosumab (Prolia®) in patients with hormone-sensitive cancer receiving endocrine therapy, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis.

This systematic review (SR) assessed the use of denosumab (Prolia®) to treat osteoporosis in cancer patients receiving endocrine therapy. Denosumab was found to prevent vertebral fractures and improve bone mineral density in cancer patients with osteoporosis. This is the first SR to assess treating osteoporotic cancer patients with denosumab. PURPOSE: This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). METHODS: Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). RESULTS: A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. CONCLUSION: In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.

Novel Treatment Options in Childhood Bone Diseases.

BACKGROUND: Several novel treatment options have recently become available in childhood bone diseases. The purpose of this article is to provide an update on some of the therapeutic agents used in the treatment of pediatric osteoporosis, X-linked hypophosphatemic rickets, and achondroplasia (ACH). SUMMARY: Vitamin D3 and Ca supplementation remains the basis of childhood osteoporosis treatment. Bisphosphonate (BP) therapy is the main antiresorptive therapeutic option, while denosumab, a human monoclonal IgG2 antibody with high affinity and specificity for a primary regulator of bone resorption - RANKL, represents a possible alternative. Its potent inhibition of bone resorption and turnover process leads to continuous increase of bone mineral density throughout the treatment also in the pediatric population. With a half-life much shorter than BPs, its effects are rapidly reversible upon discontinuation. Safety and dosing concerns in children remain. Novel treatment options have recently become available in two rare bone diseases. Burosumab, a monoclonal antibody against FGF-23, has been approved for the treatment of children with X-linked hypophosphatemic rickets older than 1 year. It presents an effective, more etiology-based treatment for rickets compared to conventional therapy, without the need for multiple daily oral phosphate supplementation. Its long-term efficacy and safety are currently being investigated. After years of anticipation, a novel treatment option for ACH has become available. C-type natriuretic peptide analog vosoritide effectively increases proportional growth and has a reasonable safety profile in children >2 years. Its effect on other features of the disease and the final height is yet to be determined. Several other treatment options for ACH exploring different therapeutic approaches are currently being investigated. KEY MESSAGES: Denosumab is effective in the treatment of childhood-onset osteoporosis; however, further studies are necessary to determine the optimal treatment protocol. Burosumab is more etiology-based and convenient in comparison to conventional treatment of X-linked hypophospha--temic rickets in children and adults. Vosoritide importantly changes the natural course of achondroplasia, at least in the short term.

Evaluation of denosumab in adult oncology patients for the prevention of skeletal related events across a large academic health system.

INTRODUCTION: Denosumab (Xgeva®) and zoledronic acid (Zometa®) are widely utilized for prevention of skeletal related events (SREs) in oncology patients. Drug costs, renal function, ease and logistics of administration, and adverse effect profile are factors frequently considered by patients and/or providers when selecting an optimal agent. Given the significantly higher drug cost of denosumab compared to zoledronic acid, an evaluation of our institution's denosumab use and investigation into opportunities to shift denosumab administrations to zoledronic acid and/or to lower cost sites-of-care was warranted. METHODS: A single-center, multi-site, retrospective, observational analysis of the electronic medical record (EMR) was conducted for adult oncology patients who received denosumab 120 mg for prevention of SREs from October 1st, 2018 to September 30th, 2019 at three institutions within our health system. Additional information was collected to characterize the patient population based on cancer diagnosis, renal function, and concomitant calcium and vitamin D supplementation. Our primary objective was to evaluate if the use of denosumab met current formulary restrictions of the health system. RESULTS: In total, 304 adult oncology patients received 1411 doses of denosumab for the prevention of SREs. The majority of reviewed patients had a primary oncology diagnosis of breast (35%) or lung (24%) cancer. Of the patients who received denosumab, 278 (93%) met the health system's current formulary restrictions. The majority of patients who did not meet formulary restrictions were those with multiple myeloma (MM) (20/22; 91%). Of the 304 patients reviewed, 70 had the appropriate parameters in the EMR to calculate creatinine clearance (CrCl) using Cockcroft-Gault Equation. Of those 70 patients, 59 (84%) would have been eligible to receive zoledronic acid instead of denosumab given that their CrCl >30 mL/min with no documented intolerance to bisphosphonates. Concurrent use of calcium and vitamin D is recommended when using denosumab. Based on the most recent prior to admission (PTA) medication list obtained from the 304 patients evaluated, 222 (73%) had both calcium and vitamin D listed as "taking". CONCLUSIONS: Within our health system, denosumab is restricted to those who meet formulary restrictions. Additional education is recommended to help limit the use of denosumab, specifically in MM, to reduce drug costs when zoledronic acid is also an appropriate first-line agent.

[Osteoprotection in patients with non-metastatic hormone-sensitive prostate cancer (mHSPC) receiving androgen-deprivation therapy (ADT): Real-world data from Germany, presented by d-uo]. / Osteoprotektion beim nichtmetastasierten hormonsensitiven Prostatakarzinom (nmHSPC) unter androgendeprivativer Therapie (ADT): Aktuelle Daten aus Deutschland, vorgelegt von d-uo.

INTRODUCTION: Patients with prostate cancer often present with reduced bone mineral density. We herein present real-world data (RWD) regarding osteoprotection in patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC) receiving androgen deprivation therapy (ADT) treated by German urologists in private practice. MATERIAL AND METHODS: This is a questionnaire-based study including members of d-uo ("Deutsche Uro-Onkologen", German uro-oncologists). Patients with nmHSPC between July 2019 and June 2020 were included. They were asked about start, type and duration of osteoprotection as well as supplementation with calcium and vitamin D. RESULTS: Between July 2019 and June 2020, a total of 3,692 patients with prostate cancer were seen at least once in one of the private practices of 15 urologists (all d-uo members). There were 844 patients (22.9%) with nmHSPC treated with ADT. Osteoprotection using denosumab or a bisphosphonate to prevent skeletal-related events (SRE) was applied in 183/844 patients (21.7%) with nmHSPC. In patients receiving osteoprotection, denosumab was chosen in 73.2% of patients and a bisphosphonate was chosen in 26.8% of patients. Supplementation with calcium and vitamin D was given in 84.7% of patients. CONCLUSION: Patients with nmHSPC received osteoprotection in 1/5 of patients. Of these, 3/4 received denosumab and 1/4 received a bisphosphonate. The majority of patients were additionally treated with calcium and vitamin D. In our study, osteoprotection in patients with nmHSPC was rather an exception.

[Osteoprotection in patients with bone metastatic castration-resistant prostate cancer (mCRPC): real-world data from Germany, presented by d-uo]. / Osteoprotektion beim ossär metastasierten kastrationsresistenten Prostatakarzinom (mCRPC): Aktuelle Daten aus Deutschland, vorgelegt von d-uo.

INTRODUCTION: Patients with bone metastasis due to prostate cancer often present allover reduced bone mineral density. Additionally, patients with bone metastatic castration-resistant prostate cancer (mCRPC) have a relevant risk for skeletal-related events (SRE). We herein present real-world data (RWD) regarding osteoprotection in mCRPC patients with bone metastasis treated by German urologists in private practice. MATERIAL AND METHODS: This is a questionnaire-based study including members of d-uo ("Deutsche Uro-Onkologen", German uro-oncologists). All patients with histologically confirmed prostate cancer seen at least once in the surveyed urology practice between July 2019 and June 2020 were included. Questions included start, type and duration of osteoprotection as well as supplementation with calcium and vitamin D. RESULTS: Between July 2019 and June 2020, a total of 3,692 patients with prostate cancer were seen at least once in 15 urology practices. There were 410 mCRPC patients (11.1%) with bone metastasis. Osteoprotection with denosumab or a bisphosphonate to prevent SRE was applied in 274/410 mCRPC patients (66.4%) with bone metastasis. In patients receiving osteoprotection, denosumab was chosen for 67.9% of patients and a bisphosphonate was chosen for 32.1%. Supplementation with calcium and vitamin D was performed in 93.4% of the patients. The median duration of treatment was 25.3 months for denosumab compared with 39.6 months for bisphosphonates. CONCLUSIONS: Patients with mCRPC with bone metastasis received osteoprotection in 2/3 of cases. Of these, 2/3 received denosumab and 1/3 received a bisphosphonate. The majority of patients were also treated with calcium and vitamin D. According to guideline recommendations regarding osteoprotection in mCRPC patients with bone metastasis, our RWD data showed some lack of guideline adherence.

Case report: Denosumab-associated acute heart failure in patients with cardiorenal insufficiency.

Denosumab is a pivotal treatment for postmenopausal women with osteoporosis. Although its clinical use is generally well tolerated by patients, denosumab in patients with renal insufficiency may increase the risk of hypocalcemia. Thus, we have to consider the population of denosumab in the treatment of osteoporosis and preventive measures for related complications. In a patient with cardiorenal insufficiency, we reported a case of denosumab-induced hypocalcemia complicated by acute left heart failure due to delayed administration of active vitamin D and calcium supplements. The patient's symptoms did not improve after anti-heart failure treatment. However, after adequate calcium and vitamin D supplementation subsequently, the patient's symptoms of heart failure were rapidly relieved, and the serum calcium level returned to normal within three weeks. Therefore, our case showed that the application of denosumab in patients requires assessment of cardiac and renal function, timely calcium and vitamin D supplementation, and enhanced monitoring of serum calcium levels to prevent acute left heart failure induced by denosumab-related hypocalcemia.

Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management.

Fractures occur in about half of older White women, and almost a third of older White men. However, 80% of the older individuals who have fractures do not meet the bone density definition of osteoporosis, suggesting that this definition is not an appropriate threshold for offering treatment. Fracture risk can be estimated based on clinical risk factors with or without bone density. A combination of calculated risk, fracture history, and bone density is used in treatment decisions. Medications available for reducing fracture risk act either to inhibit bone resorption or to promote bone formation. Romosozumab is unique in that it has both activities. Bisphosphonates are the most widely used interventions because of their efficacy, safety, and low cost. Continuous use of oral bisphosphonates for >5 years increases the risk of atypical femoral fractures, so is usually punctuated with drug holidays of 6-24 months. Denosumab is a further potent anti-resorptive agent given as 6-monthly s.c. injections. It is comparable to the bisphosphonates in efficacy and safety but has a rapid offset of effect after discontinuation so must be followed by an alternative drug, usually a bisphosphonate. Teriparatide stimulates both bone formation and resorption, substantially increases spine density, and reduces vertebral and non-vertebral fracture rates, though data for hip fractures are scant. Treatment is usually limited to 18-24 months, followed by the transition to an anti-resorptive. Romosozumab is given as monthly s.c. injections for 1 year, followed by an anti-resorptive. This sequence prevents more fractures than anti-resorptive therapy alone. Because of cost, anabolic drugs are usually reserved for those at very high fracture risk. 25-hydroxyvitamin D levels should be maintained above 30 nmol/L, using supplements if sunlight exposure is limited. Calcium intake has little effect on bone density and fracture risk but should be maintained above 500 mg/day using dietary sources.