Posted by James
The observation of the clinical cases described above could suggest that the origin of osteonecrosis has to be associated to pamidronate and zolendronate-induced insufficient vascularity. Hence, the onset of the lesions could be considered as a complication of bisphosphonate treatment as it has been shown by the literature.
In 2003 Marx and Stern were the first to describe osteonecrosis in patients suffering from multiple myeloma and treated with bisphosphonates, even though this medication had been used for more than thirty years.
No osteonecrotic lesions had been observed in the clinical trials for these drugs and this leads us to infer that other factors could contribute to the onset of lesions. The selective onset of maxillary lesions could be associated with an ecosystem of the oral cavity that can highly colonize any open wound (post-avulsion sites).
Maxillary osteonecrosis is probably due to the inability of an hypodynamic and hypovascular bone to support an increased healing demand with bone remodelling following physiological distress (chewing), iatrogenic traumas (tooth avulsions, implant surgery, periodontal operations) and tooth infections in an environment such as the oral cavity that is continuously exposed to traumas and to a strong bacterial action. Other factors could be concomitant medications with anti-angiogenic properties (such as glucocorticoids, talidomide, chemotherapeutic drugs), diabetes mellitus, maxillary irradiation, peripheral vascular disorders and clinical conditions associated with the development of osteonecrosis in any points.
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Posted by James
Treatment of patients with bisphosphonates-associated os- teonecrosis was difficult and was based on the different clinical situations. Even tough we do not have any scientific data to support a protocol for the treatment of patients with osteonecrosis treated with bisphosphonates, we are following the recommendations issued by the Expert Committee in June 2004. Our study showed a high variability of responses. Despite discontinuation of bisphosphonate treatment at the osteonecrosis diagnosis, none patient showed any improvement. The most common therapeutical approach consisted in the administration of systemic antibiotics (metronidazole 250×3 mg and moxifloxacine 400 mg/die) combined to a local clorexidine therapy followed by surgical toilette of the necrotic area or removal of the bone sequestrum.
Aggressive bone surgery was performed on three patients to remove necrotic bone tissue and to enhance healing starting from the vital bone edges.
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Posted by James
Clinical aspects
The most common clinical aspect of the lesions was mucosal ulceration with a non-vital bone exposure (Figs. 1, 2 and 3). In 1 case, we observed a mucosal fistula with a mild serosan- guineous exudation. The exposed bone was yellowish/whitish whereas the surrounding mucosa was often irritated and painful if touched (Fig. 4). On the other hand, the exposed bone did not cause any pain and did not bleed. The clinical situation showed all the features of avascular bone necrosis. Bone lesions showed a quite regular surface that in the following became irregular as a consequence of bone micro- traumatisms during chewing. In 1 case, the above mentioned irregularity produced ulcerations of the tongue edge touching the bone surface (Fig. 5). In 4 cases, bone exposed areas involved the upper maxillary at the crest and on the palate and in 5 cases the mandible on the postero-lingual and crest areas. When bone necrosis was close to the teeth, a deterioration of the local hygiene conditions was observed, with initial damage to the soft tissue with subsequent increased tooth mobility and loss. Case history revealed a previous intervention of the oral cavity, in particular tooth avulsions, insertion or removal of implants with subsequent incomplete healing of the surgical site and osteonecrosis of the post-avulsion fault.
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Posted by James
We analysed the clinical data of 9 patients demanding treatment for maxillary bone necrosis of unknown origin, sent to us by the Haematology department of the “San Giacomo” Hospital of Rome. The 9 patients belong to a group of 54 patients (41F, 13M) who were under bisphosphonate treatment for multiple myeloma, osteoporosis, hyperparathyroidism and Paget’s disease (Table I).
Table I – Group of analysed patients.
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Diagnosis
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Patient’s number
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Asymptomatic myeloma
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4
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(3F, 1M)
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|
Symptomatic myeloma
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36
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(28F, 8M)
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|
Osteoporosis
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8
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(6F, 2M)
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|
Hyperparathyroidism
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4
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(4F)
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Paget’s disease
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2
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(2M)
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|
Total
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54
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(41F, 13M)
|
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Posted by James
Clinical aspects of bisphosphonate-associated oral osteonecrosis in patients with multiple myeloma
Introduction
Bisphosphonates are non-metabolised pyrophosphonates analogues that are absorbed on the durapatite crystals of the bone matrix slowing down both growth speed and break-up by strongly inhibiting osteoclast activity.
Their clinical use dates back to 30 years ago, and in the years they have been mainly used in onco-haematology for the treatment of patients suffering from severe malignancies with bone metastasis such as lung, breast and prostate cancer, in hypercalcemia of malignancy, in the treatment of multiple myeloma and they are also prescribed in the osteoporosis and Paget’s disease.
Several bisphosphonate molecules are on the market but the most widely used in the clinical setting are pamidronate and zolendronate.
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Posted by James
The modern strategies to prevent secondary HPT in CRF patients give great relevance to vitamin D replacement therapy, which requires to take into account the stage of CRF, the underlying renal disorder, the levels of circulating PTH, the condition of the bone, the vitamin D stores, the parameters of bone turnover and the values of calcium and phosphate in serum. The administration of 1,25(OH)2D or its analogues is unavoidable in dialysis patients when secondary HPT is often already established. Its association with 25(OH)D or ergocalciferol or cholecalciferol may be beneficial for the bones, if a deficit of vitamin D stores is present (serum levels of 25(OH)D below 2030 ng/mL). Therapeutic use of 25(OH)D or ergocalciferol is indicated in earlier stages of CRF to support renal ^-hydroxylase activity. At these stages, low doses of 1,25(OH)2D may also be employed to prevent HPT since they are not harmful for renal function. The dose of vitamin D metabolites should be titrated on serum concentrations of calcium and phosphate, to avoid an excessively high calcium-phosphate product, and on serum PTH concentrations, to avoid excessive PTH suppression and an adynamic condition of the bone. The aim of vitamin D replacement therapy is to prevent HPT since the early stages of CRF, because parathyroid hyperplasia and osteodystrophy cannot be completely reverted once developed. The attention of nephrologists has largely focused on dialysis patients and, unfortunately, few studies have analyzed the outcome of vitamin D therapy in non-uremic patients. Because of the lack of clinical studies in this population no guidelines are available on when to start vitamin D replacement therapy in CRF patients. Therefore, it is likely that HPT and osteodystrophy are undertreated in a significant proportion of CRF patients. We have tried to summarize the criteria proposed in the current literature: one common criteria is that vitamin D therapy should be considered when serum 25(OH)D concentration is below 30 ng/mL. Instead, we do not know when 1,25(OH)2D can be safely prescribed to non-uremic patients and whether there are additional benefits by its association with 25(OH)D or ergocalciferol.
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Posted by James
Vitamin D analogues
Several new vitamin D analogues have been developed and investigated with the rationale to treat secondary HPT decreasing the risk of hypercalemia and hyperphosphatemia in CRF patients. Vitamin D analogues have variable affinity for the components of the vitamin D system, including the vitamin D-binding protein and the nuclear VDR. Some of the effects are genomic and mediated through changes in the structural configuration of the vitamin D-VDR complex or in the affinity of the vitamin D-VDR complex for the key response elements in various target genes. There are currently three vitamin D analogues approved for use in CRF patients with secondary HPT in the US, 1,25-dihydroxy-22-oxavitamin D3 (22-oxacalcitriol, OCT), 1,25-dihydroxy-19-norvitamin D2 (19-norD2), 1a-hydrox- yvitamin D2 (1aOHD2). 19-norD2 is approved for the treatment of secondary HPT in Italy.
OCT is a vitamin D3 derivate, which differs from 1,25(OH)2D3 for the substitution of carbon 22 with an oxygen. Oral and i.v. preparations are available. Experience in rats showed that it is less potent than 1,25(OH)2D to suppress parathyroid glands and much less active on plasma calcium. OCT is commonly administered to hemodialysis (HD) patients three times a week (Table III). In the first trial, episodes of hypercalcemia occurred in 33% of patients and serum alkaline phosphatase decreased significantly after OCT therapy, suggesting the correction of high-turnover bone disease. The reduction in PTH and the increment of calcium and phosphate were dose-dependent. The initial OCT oral dose was 5 jg three times a week when plasma iPTH concentration was 300-500 pg/mL and 10 jg three times a week when iPTH was above 500 pg/mL. OCT was also successfully used in CRF patients with creati- nine clearance above 15 mL/min at the oral dose of 1-5 jg/day with no deleterious effects on renal function. The different activity of OCT and 1,25(OH)2D has been attributed to the different pharmacokinetics of the two compounds. OCT affinity for VDR and vitamin D-binding protein is lower than that of 1,25(OH)2D and, thus, it is rapidly cleared from the blood. OCT treatment is also associated with the inhibition of renal 1 a-hydroxylase and a consequent reduction in serum levels of 1,25(OH)2D. The short half-life and the 1,25(OH)2D deficiency explain the scarce effect of OCT on intestine and bone and, ultimately, on calcium concentrations. On the other hand, OCT has a prolonged activity on parathyroid glands, where it is retained in the nuclei.
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