Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?

Ardine, Mara; Generali, Daniele; Donadio, Michela; Bonardi, S; Scoletta, Matteo; Vandone, A; Mozzati, Marco; Bertetto, Oscar; Bottini, Alberto; Dogliotti, Luigi; Berruti, Alfredo

doi:10.1093/annonc/mdl045

Cited by 47 publications

(33 citation statements)

References 5 publications

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“…Data presented by Ardine et al (33) obtained from a relatively small sample of 13 patients confirmed the results of an earlier randomized registrative study of zoledronic acid in bone metastatic breast patients in which increased PTH was noted in the first months of treatment with a progressive decrease in the later months (34). In the report by Ardine et al (33), however, patients that did develop osteonecrosis had a persistence of relative hypocalcemia and secondary hyperparathyroidism before the development of the osteonecrosis. Further study correlating serum calcium levels as well as vitamin D and PTH levels with the development of osteonecrosis of the jaw needs to be conducted to establish more significant relationships.…”

Section: Discussionsupporting

confidence: 64%

“…However, 7 out of the 14 osteonecrotic patients did have serum 1,25(OH) 2 D 3 levels less than 36 nmol/l, which is the level at which vitamin D deficiency has been defined and another 3 out of the 14 had levels between 36-75 nmol/l which is defined as vitamin D insufficiency. In other studies in patients with metastatic breast cancer, there is a suggestion that long term persistence of low serum calcium levels and high serum PTH levels during bisphosphonate treatment can predispose them to osteonecrosis of the jaw (33). Data presented by Ardine et al (33) obtained from a relatively small sample of 13 patients confirmed the results of an earlier randomized registrative study of zoledronic acid in bone metastatic breast patients in which increased PTH was noted in the first months of treatment with a progressive decrease in the later months (34).…”

Section: Discussionmentioning

confidence: 99%

“…In other studies in patients with metastatic breast cancer, there is a suggestion that long term persistence of low serum calcium levels and high serum PTH levels during bisphosphonate treatment can predispose them to osteonecrosis of the jaw (33). Data presented by Ardine et al (33) obtained from a relatively small sample of 13 patients confirmed the results of an earlier randomized registrative study of zoledronic acid in bone metastatic breast patients in which increased PTH was noted in the first months of treatment with a progressive decrease in the later months (34). In the report by Ardine et al (33), however, patients that did develop osteonecrosis had a persistence of relative hypocalcemia and secondary hyperparathyroidism before the development of the osteonecrosis.…”

Section: Discussionmentioning

confidence: 99%

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Effects of platelet-derived growth factor, vitamin D and parathyroid hormone on osteoblasts derived from cancer patients on chronic bisphosphonate therapy

Rao

Berk²,

Almojaly³

et al. 2009

Int J Mol Med

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Abstract. Bisphosphonates consist of a family of pyrophosphate analogues that are currently being used to treat metastatic bone diseases as well as systemic bone diseases such as osteoporosis. There is accumulating evidence suggesting that patients treated with these bisphosphonates can develop, particularly with invasive dental procedures, osteonecrosis of the jaw. This present study investigated the ability of osteoblastic cells obtained from the alveolar bone of patients on long term intravenous bisphosphonate therapy to respond to agents normally involved in bone regulation and repair. The effects of platelet-derived growth factor-BB (PDGF-BB), 1,25-dihydroxycholecalciferol [1,25(OH) 2 VitaminD 3 ] and parathyroid hormone (PTH) on basic parameters of cell viability, proliferation, and differentiation were studied. Osteoblastic cells from a diagnosed necrotic alveolar bone specimen obtained with consent from a multiple myeloma female patient, and a non-necrotic sample from a breast cancer female patient both on chronic bisphosphonate therapy (zolendronic acid) were successfully cultured. Cells from an alveolar bone specimen obtained from a female donor with no known medical conditions were also studied for comparative responses. The cells were exposed to 1,25(OH) 2 D 3 , PDGF, or PTH under various incubation conditions. The osteoblastic cell differentiation marker, alkaline phosphatase activity, was assayed using a biochemical analysis. Cell viability was assessed with an MTT assay which measures mitochondrial activity and cell proliferation with a tritiated thymidine assay. This study on osteoblastic cells grown from a necrotic alveolar bone from a multiple myeloma patient and a non-necrotic sample from a breast cancer patient, both on long term bisphosphonate treatment, suggests that viable cells from the bone are responsive to agents such as PTH, PDGF and 1,25(OH) 2 D 3 with changes in alkaline phosphatase activity, proliferation and viability suggestive of normal osteoblastic cell responses observed in cultures from a donor of the same gender and age, but not on bisphosphonate treatment. This work provides a rationale for clinical studies to further assess whether the osteonecrosis that sometimes develops in patients treated with bisphosphonates, can be controlled or prevented by close attention to the levels of bone/calcium regulatory agents and/or, in some cases, therapeutic intervention with PDGF to restore regenerative processes that may be compromised at the necrotic site.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of platelet-derived growth factor, vitamin D and parathyroid hormone on osteoblasts derived from cancer patients on chronic bisphosphonate therapy

Rao

Berk²,

Almojaly³

et al. 2009

Int J Mol Med

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“…70 The mechanism by which bisphosphonates may cause ONJ remains unclear. Ardine et al 71 reported that patients with bisphosphonate-associated ONJ had persistently higher PTH levels compared to controls without ONJ and they suggested that high PTH may be involved in the pathogenesis of ONJ. Evidence against this theory is that in patients with primary hyperparathyroidism and elevated PTH, lesions in the oral cavity include reduced radicular lamina dura, reduced interdental alveolar bone density and reduced cortical bone at the gonial index, 72 whereas the bisphosphonate-associated ONJ is characterized by osteopetrosis-like osseous sclerosis with thickening of the lamina dura and of the alveolar crest and sclerosis of the alveolar margin.…”

Section: Osteonecrosis Of the Jawmentioning

confidence: 99%

Bisphosphonate-associated adverse events

Papapetrou

2009

259

174

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The adverse events of the nitrogen-containing bisphosphonates are reviewed. Oral bisphosphonates (alendronate, risedronate and ibandronate), mainly used for the treatment of osteoporosis, have been associated with adverse events from the upper gastrointestinal tract, acute phase response, hypocalcaemia and secondary hyperparathyroidism, musculoskeletal pain, osteonecrosis of the jaw and ocular events. Intravenous bisphosphonates (pamidronate, ibandronate and zoledronic acid), used in oncology and for the treatment of osteoporosis, have been associated with all the above adverse events, except those from the upper gastrointestinal tract. Moreover, pamidronate and zoledronic acid have been associated with renal toxicity. Association of bisphosphonates with atrial fibrillation and atypical fractures of the femoral diaphysis remains uncertain. There are a few case reports relating bisphosphonates to cutaneous reactions, oral ulcerations, hepatitis and esophageal cancer. Generally, intravenous are more potent than oral bisphosphonates and the frequency and severity of some of the bisphosphonate-associated adverse events are dose and potency dependent.

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“…In 2006, Ardine et al [26] reported that patients with BRONJ had persistently higher parathyroid hormone (PTH) levels compared to normals and suggested that higher PTH level may involve in the pathogenesis of osteonecrosis of the jaw. While in 2009, Papapetrou [3] reported in some cases of BP related secondary hyperthyroidism that there may be a relatively smaller reduction of bone turnover caused by the BPs because of the antagonistic effect of the high PTH.…”

Section: Aetiopathogenesis Of Bisphosphonate Related Osteonecrosis Ofmentioning

confidence: 99%

Bisphosphonate Related Osteonecrosis of the Jaw: An Update

Kumar¹,

Sinha²

2013

J. Maxillofac. Oral Surg.

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Objectives The aim of this paper is to summarize different diagnostic criteria as well as probable aetiopathogenesis of bisphosphonates related osteonecrosis of the jaw. Materials and MethodsThe electronic search of peerreviewed journals were performed in MEDLINE (PubMed) database in order to find the relevant articles on bisphosphonates related osteonecrosis of the jaw (BP-related ONJ). The search was restricted to English language articles, published from January 2002 to May 2013. On the basis of these articles, probable aetiopathogenesis and different diagnostic criteria of BP-related ONJ were summarized. Results BP-related ONJ is related to the development of avascular necrosis or dead jaw bones. In recent literature many given hypotheses show the aetiopathogenesis and diagnosis of BP-related ONJ which are interlinked and have multifactorial nature. Their diagnosis revolves around four main diagnostic criteria that differentiate it from other conditions which can delay bone healing. Conclusions Factors like potency of bisphosphonates, biology of jaw bone, antiangiogenic property of bisphosphonates and soft tissue toxicity in combination with present infection, other drugs, pre-existing pathologies, compromised immune response and dentoalveolar trauma may lead to development of BP-related ONJ.

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Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?

Cited by 47 publications

References 5 publications

Effects of platelet-derived growth factor, vitamin D and parathyroid hormone on osteoblasts derived from cancer patients on chronic bisphosphonate therapy

Effects of platelet-derived growth factor, vitamin D and parathyroid hormone on osteoblasts derived from cancer patients on chronic bisphosphonate therapy

Bisphosphonate-associated adverse events

Bisphosphonate Related Osteonecrosis of the Jaw: An Update

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