Denosumab Research Articles

Denosumab Induced Severe Prolonged Hypocalcemia in Metastatic Prostate Cancer

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.

Rebound Hypercalcemia After Denosumab Therapy in a Child With Cherubism

Background: Cherubism, caused by autosomal dominant mutations in the SH3BP2 gene, is characterized by increased bone resorption with development of bilateral fibro-osseous lesions limited to the maxilla and mandible. The SH3BP2 gene is thought to be involved in osteoclastogenesis. Affected children, while usually asymptomatic at birth, typically present at 2–5 years of age with cheek and jaw swelling with upward tilting of eyes due to expansion of fibrous tissues. Bone resorption and proliferation of lesions continues until puberty after which spontaneous regression occurs. RANKL is a cytokine expressed on the surface of osteoclast precursors and is responsible for inducing osteoclast differentiation. Denosumab is an anti-RANKL monoclonal antibody which prevents osteoclast maturation. However, it has a short half-life, and effects on bone turnover have been found to be rapidly reversible after drug discontinuation. The rebound increased bone turnover can lead to severe hypercalcemia. Clinical Case: A 4 year old boy with cherubism (c.1253C>G pathogenic variant in SH3BP2), after failing a 10-month trial of tacrolimus, was placed on monthly denosumab (2 mg/kg) for a total of 10 doses. During denosumab therapy, he received calcium and vitamin D to prevent hypocalcemia; these were stopped once denosumab was discontinued. He presented to the hospital 4 months after the final denosumab dose with polyuria, polydipsia, fatigue, nausea and abdominal pain. Work-up revealed serum Ca 15.3 mg/dL (N: 8.4–10.2), PTH <3 pg/mL (N: 24–86), 25-OH vitamin D 32 ng/mL (N: >19 ng/mL), 1,25-dihydroxyvitamin D 6.7 pg/mL (N: 19.9–79.3), and urine Ca/Cr 0.48. Renal ultrasound showed normal kidneys with a small amount of layering debris in the bladder. During hospitalization, he received IV fluids, 1 dose of furosemide, 3 doses of calcitonin, 24 hours of hydrocortisone, and a single 0.5 mg/kg dose of pamidronate. He was discharged 48 hours after the bisphosphonate with serum Ca 9.5 mg/dL. He returned with serum Ca 13.5 mg/dL 9 days after the pamidronate and was readmitted. He again received 4 doses of calcitonin and 1 dose of pamidronate (0.5 mg/kg). Calcium levels improved to 9.5 mg/dL at discharge but rose to 11.6 mg/dL a week later. He received a 0.05 mg/kg dose of zoledronate outpatient, with improvement in serum Ca to 10.1 mg/dL. A week later, he twisted his ankle, resulting in transverse impacted buckle fractures of his left distal tibia and fibula; no lytic or sclerotic lesions were noted on x-ray. His leg was immobilized by Orthopedics. Calcium levels remained within range (9.9 mg/dL) 7 months after the zoledronate. Conclusion: Rebound hypercalcemia can occur months after denosumab withdrawal, indicating the need for close monitoring of calcium levels in patients who receive this drug. The hypercalcemia appears to respond best to bisphosphonates, with a more sustained response to zoledrenate compared to pamidronate.

An adiponectin receptor agonist promote osteogenesis via regulating bone-fat balance.

ObjectivesAdiponectin signalling has been considered to be a promising target to treat diabetes‐related osteoporosis. However, contradictory results regarding bone formation were observed due to the various isoforms of adiponectin. Therefore, it would be necessary to investigate the effect of adiponectin receptor signals in regulating bone‐fat balance.Materials and MethodsWe primarily applied a newly found specific activator for adiponectin receptor, AdipoRon, to treat bone metabolism‐related cells to investigate the role of Adiponectin receptor signals on bone‐fat balance. We then established femur defect mouse model and treated them with AdipoRon to see whether adiponectin receptor activation could promote bone regeneration.ResultsWe found that AdipoRon could slightly inhibit the proliferation of pre‐osteoblast and pre‐osteoclast, but AdipoRon showed no effect on the viability of mesenchymal stromal cells. AdipoRon could remarkably promote cell migration of mesenchymal stromal cells. Additionally, AdipoRon promoted osteogenesis in both pre‐osteoblasts and mesenchymal cells. Besides, AdipoRon significantly inhibited osteoclastogenesis via its direct impact on pre‐osteoclast and its indirect inhibition of RANKL in osteoblast. Moreover, mesenchymal stromal stems cells showed obviously decreased adipogenesis when treated with AdipoRon. Consistently, AdipoRon‐treated mice showed faster bone regeneration and repressed adipogenesis.ConclusionsOur study demonstrated a pro‐osteogenic, anti‐adipogenic and anti‐osteoclastogenic effect of adiponectin receptor activation in young mice, which suggested adiponectin receptor signalling was involved in bone regeneration and bone‐fat balance regulation.

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Osteonecrose dos maxilares relacionada ao uso de medicamentos: Revisão sistemática

A osteonecrose dos maxilares relacionada ao uso de medicamentos (OMRM) é uma situação clínica, proveniente de efeitos secundários da terapêutica com alguns fármacos, como os bifosfonatos, os inibidores do RANK-L e alguns antiangiogênicos. O objetivo do presente trabalho foi realizar uma revisão sistemática sobre OMRM. As pesquisas realizadas permitiram a seleção de 9 artigos, a partir de 759 artigos encontrados. Os resultados do presente estudo mostram que a doença subjacente mais comum foi o câncer de mama, a via de administração mais prevalente foi a intravenosa, extração dentária foi o principal procedimento odontológico desencadeador e a região mais acometida pela alteração foi a mandíbula. O atendimento pelo cirurgião-dentista é fundamental antes do início da terapia com os medicamentos estudados, principalmente, com o bifosfonatos.

Effects after starting or switching from bisphosphonate to romosozumab or denosumab in Japanese postmenopausal patients.

PurposeWe aimed to investigate the longitudinal changes in bone metabolic markers and bone mineral density (BMD) after starting or switching from bisphosphonate (BP) to romosozumab (ROMO) or denosumab (DENO) therapies over 12 months and to determine predictors that establish associations with changes in BMD among the patients received the ROMO therapy.MethodsPostmenopausal osteoporosis patients with a high risk of fracture—154 in total—were recruited; their therapies were switched to ROMO or DENO from BP/naïve or vitamin D (ND) (ND-ROMO: 43, BP-ROMO: 38, ND-DENO: 38, and BP-DENO: 35). Longitudinal changes in bone metabolic markers and BMD were evaluated.ResultsROMO groups showed significant increases in BMD of the lumbar spine at 6 and 12 months and femoral neck at 12 months compared to the DENO groups. Although BP-ROMO showed significant increase in the lumbar spine BMD compared to BP-DENO, there were no significant differences in femoral neck and total hip BMDs between BP-ROMO and BP-DENO. Among the ROMO groups, % changes of BMD from baseline to 12 months were associated with bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months.ConclusionsROMO continuously increased BMD for 12 months and performed better than DENO. On the other hand, effects of ROMO switched from BP on BMD of femoral neck and total hip were almost same with DENO. Bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months may predict the efficacy of ROMO after 12 months of administration.

Short-term efficacy and safety of zoledronate acid or denosumab in Japanese patients with postmenopausal osteoporosis

IntroductionWe aimed to compare the efficacy after switching from either bisphosphonates (BPs) or non-BPs (NBPs) to combination therapies of denosumab (DMAb) or zoledronic acid (Zol) with eldecalcitol (ELD) in bone mineral density (BMD) and bone metabolism and investigate the prognostic and risk factors of side effects of this therapy.Materials and methodsOne-hundred forty-eight patients with postmenopausal osteoporosis were recruited; their therapy was switched from BPs or NBPs to Zol or DMAb plus ELD (BP-Zol: 43, NBP-Zol: 32, BP-DMAb: 35, and NBP-DMAb: 38). Longitudinal changes in bone metabolic markers (P1NP and TRACP-5b) and BMD were evaluated.ResultsIn the BP-Zol group, P1NP did not change after 6 months and increased by 38.9% after 12 months. TRACP-5b decreased 15.8% after 6 months, but came back to baseline values 12 months after administration. In the rest of the groups, the bone metabolic markers remained suppressed after 6 and 12 months. Compared with baseline, all groups showed increase in BMD after 6 and 12 months. Bone metabolic markers at baseline were correlated with %change in lumbar spine BMD from baseline to 12 months. P1NP and 25-hydroxy vitamin D levels at baseline were identified as potential predictors of development of acute-phase reactions.ConclusionsThe combination therapy of Zol or DMAb and ELD may increase BMD at 12 months after the first administration in Japanese patients with postmenopausal osteoporosis, regardless of BPs pretreatment. Bone metabolic markers at baseline may be useful predictors for reaction to the therapy and side effects caused by these combination therapies in postmenopausal osteoporosis.

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POS-689 BONE EFFECT AND SAFETY OF ONE-YEAR DENOSUMAB THERAPY IN A COHORT OF RENAL TRANSPLANTED PATIENTS: AN OBSERVATIONAL MONOCENTRIC STUDY

Our study evaluated the effects of one year-treatment with Denosumab (DB) on bone mineral density (BMD), FRAX SCORE, mineral metabolism (MM) parameters and safety in 32-kidney transplanted patients (KTxps).

Anti-IL17 antibody Secukinumab therapy is associated with ossification in giant cell tumor of bone: a case report of pathologic similarities and therapeutic potential similar to Denosumab

BackgroundGiant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage.Case presentationOne case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB.ConclusionsSecukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease.

Schistosome infection promotes osteoclast-mediated bone loss.

Infection with schistosome results in immunological changes that might influence the skeletal system by inducing immunological states affecting bone metabolism. We investigated the relationships between chronic schistosome infection and bone metabolism by using a mouse model of chronic schistosomiasis, affecting millions of humans worldwide. Results showed that schistosome infection resulted in aberrant osteoclast-mediated bone loss, which was accompanied with an increased level of receptor activator of nuclear factor-κB (NF-κB) Ligand (RANKL) and decreased level of osteoprotegerin (OPG). The blockade of RANKL by the anti-RANKL antibody could prevent bone loss in the context of schistosome infection. Meanwhile, both B cells and CD4+ T cells, particularly follicular helper T (Tfh) cell subset, were the important cellular sources of RANKL during schistosome infection. These results highlight the risk of bone loss in schistosome-infected patients and the potential benefit of coupling bone therapy with anti-schistosome treatment.

RANKL Mediates Muscle Atrophy and Dysfunction in a Cigarette Smoke-induced Model of Chronic Obstructive Pulmonary Disease.

Skeletal muscle dysfunction is one of the important comorbidities of chronic obstructive pulmonary disease (COPD); however, the underlying mechanisms remain largely unknown. RANKL (receptor activator of nuclear factor κB ligand), a key mediator in osteoclast differentiation, was also found to play a role in skeletal muscle pathogenesis. Whether RANKL is involved in COPD-related skeletal muscle dysfunction is as-of-yet unknown. We examined the expression of RANKL/RANK in skeletal muscles from mice exposed to cigarette smoke (CS) for 24 weeks. Grip strength and exercise capacity as well as muscular morphology were evaluated in CS-exposed mice with or without anti-RANKL treatment. The expressions of protein synthesis- or muscle growth-related molecules (IGF-1, myogenin, and myostatin), muscle-specific ubiquitin E3 ligases (MuRF1 and atrogin-1), and the NF-κb inflammatory pathway were also evaluated in skeletal muscles. The effect of CS extract on RANKL/RANK expression and that of exogenous RANKL on the ubiquitin-proteasome pathway in C2C12 myotubes were investigated in vitro. Long-term CS exposure induced skeletal muscle dysfunction and atrophy together with upregulation of RANKL/RANK expression in a well-established mouse model of COPD. RANKL neutralization prevented skeletal muscle dysfunction and atrophy. RANKL inhibition decreased expressions of myostatin and MuRF1/Atrogin1 and suppressed the NF-κb pathway in skeletal muscles from CS-exposed mice. In in vitro experiments with C2C12 myotubes, CS extract induced expression of RANKL/RANK, and exogenous RANKL induced activation of the ubiquitin-proteasome pathway and NF-κb pathway via RANK. Our results revealed an important role of the RANKL/RANK pathway in muscle atrophy induced by CS exposure, suggesting that RANKL may be a potential therapeutic target in COPD-related skeletal muscle dysfunction.

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