Long-term Bisphosphonate Administration Research Articles

Encounter of cancer cells with bone. Present status and problems in occurrence of bisphosphonate-related osteonecrosis of the jaws

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) develops as a side effect of long-term administration of bisphosphonates (BP) , especially intravenous preparations. The lesion is a new disease entity which was first reported in 2003 in the United States. Since then, the number of patients with BRONJ is increasing year by year. In Japan, the first case was reported in 2006, and at that time 30 cases of BRONJ were registered in the nationwide survey by the Japanese Society of Oral and Maxillofacial Surgeons. However, the patients with BRONJ increased rapidly in the second survey after 2 years, and more than 250 cases of BRONJ which met the criteria of clinical diagnosis were determined. Approximately 95% of the BRONJ patients received intravenous BPs and less than 5% received oral BPs in the United States and European Union, whereas 58% of the patients received intravenous BPs and 40% received oral BPs in Japan. The relative ratio of BRONJ associated with the use of oral BPs was higher in Japan than in the United States and European Union. BRONJ is refractory to treatment, and an efficient and useful therapy is not yet established.

Bisphosphonates Cause Osteonecrosis of the Jaw-Like Disease in Mice

Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a morbid bone disease linked to long-term bisphosphonate use. Despite its broad health impact, mechanistic study is lacking. In this study, we have established a mouse model of BONJ-like disease based on the equivalent clinical regimen in myeloma patients, a group associated with high risk of BONJ. We demonstrate that the murine BONJ-like disease recapitulates major clinical and radiographical manifestations of the human disease, including characteristic features of osseous sclerosis, sequestra, avascular, and radiopaque alveolar bone in the jaw that persists beyond a normal course of wound healing following tooth extraction. We find that long-term administration of bisphosphonates results in an increase in the size and number of osteoclasts and the formation of giant osteoclast-like cells within the alveolar bone. We show that the development of necrotic bone and impaired soft tissue healing in our mouse model is dependent on long-term use of high-dose bisphosphonates, immunosuppressive and chemotherapy drugs, as well as mechanical trauma. Most importantly, we demonstrate that bisphosphonate is the major cause of BONJ-like disease in mice, mediated in part by its ability to suppress osseous angiogenesis and bone remodeling. The availability of this novel mouse model of BONJ-like disease will help elucidate the pathophysiology of BONJ and ultimately develop novel approaches for prevention and treatment of human BONJ.

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Long-term and high-dose bisphosphonate administration causes no bone over-mineralization

To evaluate the effects of long-term bisphosphonate administration (incadronate) upon the mean degree of secondary bone mineralization. Thirty adult beagles were divided randomly into three groups of CNT, YML and YMH based upon their body weights (5 males and 5 females in each group). Animals in CNT were orally given lactose 12 mg x kg(-1) x d(-1) while those in YML and YMH were orally given incadronate disodium at doses of 0.3 mg x kg(-1) x d(-1) and 0.6 mg x kg(-1) x d(-1) respectively. The dosing procedure lasted for three years. Prior to sacrifices, all animals were double-labeled intravenously with oxytetracycline hydrochloride (20 mg x kg(-1)). After necropsy, the left 9th ribs were excised for evaluation. Histomorphometry showed that activation frequency in YML and YMH [(4.93 +/- 0.92)/mm(2) and (2.50 +/- 0.78)/mm(2)] were significantly lower than that in CNT (7.83 +/- 0.96)/mm(2) per year. The mean degree of mineralization in bone in YML and YMH (1.40 +/- 0.12, 1.48 +/- 0.09) were significantly higher than CNT (1.07 +/- 0.06). The increments were 31% and 38% respectively. Long-term and high-dose bisphosphonate administration significantly suppresses bone turnover so as to increase the degree of bone mineralization. But there is no resulting bone over-mineralization. (incadronate) administration on the mean degree of secondary mineralization in bone.

Does long-term bisphosphonate administration cause over-mineralization?

Results: Micro-CT revealed no significant differences for skeletal microstructures between the OVX and the shamgroup at 2weeks postoperation in both 12and 24-week old rats. Trabeculae were significantly thinner in 24-week old rats (both OVX and sham) in comparison with their younger counterparts. In 12-week old rats the skeletal microstructure changed and started to show differences between the OVX and the sham groups from week 5 post-operation and the differences had not reached the plateau by week 15 post-operation. Conclusions: This study investigated the short and long-term effects of OVX on changes in bone architecture at multiple skeletal sites in young and middle aged rats. Different bone architecture in different aged rats may lead to a different dynamic changes post-OVX. Histological analysis of the trabeculae may provide insight information on anabolic and/or catabolic cascades of OVX.

High Concentrations of Pamidronate in Bone Weaken the Mechanical Properties of Intact Femora in a Rat Model

PurposeBisphosphonates have been used to treat osteoporosis for more than ten years. However, complications associated with long-term administration of bisphosphonates, such as nonunion after pelvic insufficiency fracture or osteonecrosis of the jaw, have been recently reported in the literature. We investigated the relationships among the mechanical properties of the intact rat femur as well as healing fracture calluses and the intraosseous concentration of pamidronate (ICP), after long-term administration of pamidronate in a rat osteoporosis model.Materials and MethodsWe performed bilateral ovariectomy in 25 3-month-old female Sprague-Dawley rats. Beginning three months after ovariectomy, disodium pamidronate (0.5mg/kg) was injected every month. After the six-month administration period, the left femoral shaft was fractured using the closed fracture technique. Five weeks after fracture, 23 rats were euthanized and both femora were removed. We checked the mechanical properties of the intact (right) and fractured (left) femora using a three-point bending technique. Intraosseous concentration of pamidronate was checked by high-performance liquid chromatography.ResultsThe mean ICP was 61.8 ± 15.7ng/mg of bone. High ICP decreased the ultimate load to failure, stiffness, and ultimate stress of the intact femora (p = 0.015, 0.027, 0.039, respectively). There was a tendency to decrease the ultimate load to failure in the healing callus when the ICP increased (p = 0.183). High ICP decreased the bone mineral density of the femoral head (p = 0.005).ConclusionHigh concentrations of pamidronate in intact bone decreased the bone mineral density and weakened the mechanical strength of the rat femora. The mechanical strength of the early healing callus was not correlated with concentration of pamidronate in the bone.

Long-term bisphosphonate administration and its effect on bone metabolism

Since bisphosphonates (BPs) suppress bone turnover, potential concerns regarding bone metabolism during long term BP administration have been raised. Now up to 10 years follow-up of clinical trials with data of bone metabolism are available. There was no adverse effect on bone metabolism with long term BP treatment, and increase in bone mineral density and reduction in fracture risk were retained.

Safety of Long-Term Administration of Bisphosphonates in Elderly Cancer Patients

Background: To evaluate the effectiveness and tolerability of the long-term treatment bone metastases with pamidronate in older patients. Materials and Methods: Twenty-two ambulatory patients aged 70 or older were included in the study. The median age was 73 (range 70–77). Ten patients (46%) were affected by breast carcinoma, 7 (32%) by prostate carcinoma and 5 (22%) by multiple myeloma. Nine (40%) patients presented co-morbidity. All of the patients presented at least one metastatic lytic bone lesion measuring 1 cm or more in diameter; the median lesion number was 2 (range 1–4). Hormonal therapy or chemotherapy regimen, were allowed as clinically required. Patients were treated with a fixed dose of sodium pamidronate, 90 mg in 3 h infusion every 4 weeks. Results: Partial response was shown in 6 (28%) patients, stable disease in 11 (50%), and progression (PD) in 5 (22%). 2 out of 5 patients with PD presented skeletal-related events (SREs) such as bone fracture. The median treatment duration was 19 months. The treatment was well tolerated; in 5 patients (23%) a GI fever was observed, in 3 patients (18%) G1 nausea, and in 3 patients (14) G1 diarrhea. Two cases (9%) of acute renal insufficiency (creatinine 1.7 and 1.6 mg/dl), and 3 cases (14%) of hypocalcemia (7.6, 7.5 and 7.8 mg/dl) were also registered. The renal dysfunction was reversible and without consequence. Conclusion: Our experience suggests that the bisphosphonates long-term administration is useful and did not cause significant side effects in elderly subjects. Low-grade pyrexia, nausea/vomiting, acute/reversible renal dysfunction and hypo-calcemia were the most frequent side effects reported. However, they were of low grade and in most cases, did not require dose modifications and/or hospitalization.