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

Pittman, K.; Antill, Yoland; Goldrick, Amanda; Goh, Jeffrey C.; Boer, Richard H. De

doi:10.1111/ajco.12517

Cited by 48 publications

(45 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has been reported that adequate vitamin D and calcium supplementation reduce the risk of hypocalcaemia . When denosumab was launched, the standard treatment for denosumab‐induced hypocalcaemia was not established.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that adequate vitamin D and calcium supplementation reduce the risk of hypocalcaemia. 16,17 When denosumab was launched, the standard treatment for denosumab-induced hypocalcaemia was not established. Additionally, although native vitamin D 3 supplements were used in a clinical trial in Japan, 18 they were not listed in the National Health Insurance drug price list in Japan.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

et al. 2019

View full text Add to dashboard Cite

What is known and Objective Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication (‘Blue letter’) was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan by using an electronic medical information database (MID). Methods We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. Results and Discussion The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. What is New and Conclusion There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab‐induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

et al. 2019

View full text Add to dashboard Cite

show abstract

“…103,104 The risk of developing hypocalcemia as a result of treatment with bisphosphonates or denosumab can be reduced by intake of sufficient dietary or supplemental calcium. 105,106 Risk factors for MRONJ The dominant factor when assessing the likelihood of development of MRONJ is the cumulative exposure of the patient to bisphosphonates or denosumab, considering both the dose per treatment and the number of administrations given from the start of the treatment. 78,79,107 To date, however, no clear threshold below which MRONJ does not occur has been identified.…”

Section: Hypercalcemia Of Malignancymentioning

confidence: 99%

Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment

Nicolatou‐Galitis

Schiødt

Mendes

et al. 2019

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

241

203

View full text Add to dashboard Cite

Skeletal complications caused by osteoporosis or bone metastases are associated with considerable pain, increased mortality, and reduced quality of life. Furthermore, such events place a burden on health care resources. Agents that prevent bone resorption, such as bisphosphonates or denosumab, can reduce the risk of skeletal-related events and are widely used in patients with osteoporosis or bone metastases of cancer. Medication-related osteonecrosis of the jaw (MRONJ) is a rare, but potentially serious, adverse event associated with high cumulative doses of bisphosphonates or denosumab. However, MRONJ can be treated, and the likelihood of the development of this condition can be reduced through prophylactic dental care and the maintenance of good oral hygiene. Dentists, as part of a multiprofessional team, have a critical role in preventing MRONJ. This review describes the incidence and pathophysiology of MRONJ and provides guidance for dental practitioners with regard to the screening, prophylactic treatment, diagnosis, and management of patients with this condition. (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;127:117À135) Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon condition that can occur after exposure to agents used to prevent bone complications, such as bisphosphonates or denosumab, or treatment with other agents, such as angiogenesis inhibitors. 1 In the majority of cases, MRONJ manifests as exposed bone in the maxillofacial region (Figure 1), although non-exposed MRONJ has also been recognized (Figure 2). 2-5 Bisphosphonates and denosumab are predominantly used to reduce the risk of skeletal complications in patients with bone loss, resulting from long-term cancer treatment or osteoporosis, and in patients with malignant bone disease. 6-8 Bisphosphonates are small molecules that dock in hydroxyapatite-binding sites on bone surfaces. When osteoclasts begin to resorb bisphosphonate-impregnated bone, the liberated bisphosphonates bind to farnesyl pyrophosphate synthase inside the osteoclasts, ultimately leading to apoptosis. 8-10 Denosumab is a fully human monoclonal antibody, which has a different mode of action from that of bisphosphonates. It targets and binds to the receptor activator of nuclear factor k-B (RANK) ligand (RANKL); in doing so it prevents the activation of RANK on the surface of osteoclasts and osteoclast precursors. Inhibition of the RANKLÀRANK interaction impedes osteoclast formation, function, and survival, thereby decreasing bone resorption. 11 MRONJ is more prevalent among patients receiving high cumulative doses of bisphosphonates or denosumab than in patients who receive lower doses. 12,13 The first cases Statement of Clinical Relevance Medication-related osteonecrosis of the jaw is a rare, but potentially serious, complication of treatment with bisphosphonates and denosumab. It is important for dentists to be aware of ways to identify and treat patients at risk of this condition.

show abstract

“…The mechanism of denosumab-induced hypocalcemia consists of inhibition of osteoclast function, causing a decrease in the efflux of calcium from the bone to the blood. 15 To prevent such hypocalcemia, calcium, and vitamin D supplementation and regular monitoring of serum calcium concentration are necessary. Provitamin D3 is converted to vitamin D3 by ultraviolet rays and then metabolized to activated vitamin D3 in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Activated vitamin D3 formulations can be safely used as concomitant medication for prevention of denosumab‐induced hypocalcemia in women with postmenopausal osteoporosis

Saito

Sugo

Tsuburai

et al. 2019

J of Obstet and Gynaecol

View full text Add to dashboard Cite

Aim Denosumab prevents osteoporosis by potently inhibiting bone resorption, but requires oral therapy with calcium and vitamin D preparations to prevent the side effects of hypocalcemia. Generally, a combination drug containing calcium, natural vitamin D, and magnesium is used. However, if activated vitamin D has been used before the initiation of denosumab therapy, continued use of activated vitamin D is not uncommon. This study aimed to evaluate the combination vitamin D preparation, alfacalcidol, and eldecalcitol on the therapeutic effect on denosumab therapy, the preventive effect on hypocalcemia, and the effect on renal function, to determine the optimal choice of concomitant medication. Methods This is a retrospective and single‐center study. Among 39 patients who had used denosumab (60 mg dose) for at least 12 months between November 2013 and October 2015, those who used the combination medication concomitantly as the standard treatment, those who used alfacalcidol concomitantly, and those who used eldecalcitol concomitantly were compared. Results Denosumab therapy markedly increased lumbar spine and femoral neck bone densities at 12 months in the three groups, showing no particular difference in the rate of increase of bone density. The three groups had marked decreases in bone metabolism markers, but had no intergroup differences. No hypocalcemia, hypercalcemia, or obvious renal dysfunction occurred over 12 months. Conclusion This study indicates that the use of activated vitamin D preparations, as concomitant medications with denosumab therapy, is appropriate considering the therapeutic efficacy of denosumab, prevention of hypocalcemia, and influence on renal function.

show abstract

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

Cited by 48 publications

References 46 publications

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment

Activated vitamin D3 formulations can be safely used as concomitant medication for prevention of denosumab‐induced hypocalcemia in women with postmenopausal osteoporosis

Contact Info

Product

Resources

About