Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management

Kennel, Kurt A.; Drake, Matthew T.

doi:10.4065/84.7.632

Cited by 228 publications

(87 citation statements)

References 32 publications

(21 reference statements)

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“…(42) However, N-BPs target a wide range of small GTPases that control many signaling cascades, which may be a reason for the undesirable side effects arising from N-BPs-based treatments. (43,44) Considerable effort is currently being made to develop novel antiresorptive agents by targeting processes more specific to OCs, such as RANKL antibodies and cathepsin K inhibitors. (45) We found that Dock5 is expressed predominantly in OCs; in particular, it is not expressed in osteoblasts, the bone-forming cells.…”

Section: Discussionmentioning

confidence: 99%

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

Vives

Laurin

Crès

et al. 2010

Journal of Bone and Mineral Research

106

148

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Osteoporosis, which results from excessive bone resorption by osteoclasts, is the major cause of morbidity for elder people. Identification of clinically relevant regulators is needed to develop novel therapeutic strategies. Rho GTPases have essential functions in osteoclasts by regulating actin dynamics. This is of particular importance because actin cytoskeleton is essential to generate the sealing zone, an osteoclast-specific structure ultimately mediating bone resorption. Here we report that the atypical Rac1 exchange factor Dock5 is necessary for osteoclast function both in vitro and in vivo. We discovered that establishment of the sealing zone and consequently osteoclast resorbing activity in vitro require Dock5. Mechanistically, our results suggest that osteoclasts lacking Dock5 have impaired adhesion that can be explained by perturbed Rac1 and p130Cas activities. Consistent with these functional assays, we identified a novel small-molecule inhibitor of Dock5 capable of hindering osteoclast resorbing activity. To investigate the in vivo relevance of these findings, we studied Dock5 -/-mice and found that they have increased trabecular bone mass with normal osteoclast numbers, confirming that Dock5 is essential for bone resorption but not for osteoclast differentiation. Taken together, our findings characterize Dock5 as a regulator of osteoclast function and as a potential novel target to develop antiosteoporotic treatments. ß

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Section: Discussionmentioning

confidence: 99%

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

Vives

Laurin

Crès

et al. 2010

Journal of Bone and Mineral Research

106

148

View full text Add to dashboard Cite

show abstract

“…A recently published example of this situation comes from the use of bisphosphonates to treat osteoporosis. Although the benefits of these drugs outweigh the potential costs, their use trades off a reliable benefit through reduced hip and spine fractures against a very rare side effect causing deterioration of the lower jaw (Kennel and Drake, 2009;Crandall, Newberry et al, 2014;Jha, Wang et al, 2015). Our ABM demonstrates that at short time scales the first outcome will dominate, while at longer time scales the rare, negative outcome will affect decision making.…”

Section: Class 2 Models-confirming Behavior: Both Behaviors Are Selfrmentioning

confidence: 93%

“…The Watts-Strogatz (Watts and Strogatz, 1998;Kennel and Drake, 2009) networks, also known as "small-world" networks, are a useful class of model networks that we can use to explore the stability of network clusters. Examples of this network structure are shown in Figure 4.8.…”

Section: Class 2 Models-confirming Behavior: Both Behaviors Are Selfrmentioning

confidence: 99%

A General Agent-Based Model of Social Learning

Nowak¹,

Matthews²,

Parker³

2017

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“…Hypocalcaemia is caused by the inhibition of osteoclastic activity that reduces the availability of calcium from this source [4,20,30,31]. Minor asymptomatic hypocalcaemia in children on pamidronate therapy has been reported by many investigators [12,32].…”

Section: Discussionmentioning

confidence: 99%

“…It is important to highlight that hypovitaminosis needs to be corrected and parathyroid hormone levels restored to normal prior to starting pamidronate therapy, as is our practice now [20]. Hypocalcaemia is treated by replacement doses of oral calcium and vitamin D, and may need to be continued for several months [5,20,31].…”

Section: Discussionmentioning

confidence: 99%

Complications of pamidronate therapy in paediatric osteoporosis

Chilbule

Madhuri

2012

Journal of Children's Orthopaedics

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Purpose Pamidronate, used for the treatment of paediatric osteoporosis, reduces the fracture rate and improves ambulatory status. Intravenous pamidronate therapy has known complications which have not been stratified based on its dose and distribution. This study aims to assess the early minor and major medical and late surgical complications and the effect of the dose and regimen of infusion on these events in paediatric osteoporosis. Study design Retrospective cohort. Materials and methods Three regimens for pamidronate infusion were followed in sequential periods in 10 years. Regimen A delivered 1.5 mg/kg/day as a single dose once in 3 months. Regimen B delivered 2 mg/kg/day for 3 days twice a year, while regimen C delivered 1 mg/kg/day for 3 days every 3-4 months. Adverse events were classified as early (major and minor) or late (surgical). Results Forty-eight children received 158 infusions using one of the three regimens. Twenty-nine complications occurred in 24 children. A significant difference in the complication rate was present among the three regimens (P = 0.005). Nineteen children had minor complications, mainly febrile reaction or asymptomatic hypocalcaemia. Four major complications consisting of one seizure, one respiratory distress and two hypocalcaemic tetany were encountered, all with regimen B. Intraoperative complication faced was loss of position due to splintering of the cortex while rush rodding. This was seen in 20% of the long bone segments operated in those who received pamidronate as compared to 4.4% of the segments which were operated prior to the initiation of pamidronate therapy; the odds of splintering were 5.4 times higher for those patients who were bone segment rodded after pamidronate therapy. Discussion Intravenous pamidronate is associated with complications in 50% of children with paediatric osteoporosis, with a dose-dependent significant difference. Major complications are not uncommon with higher doses and can be avoided by increasing the number of doses per year and decreasing the dose per cycle. Surgical difficulty, when possible, can be avoided by correcting any major deformities at presentation prior to the induction of pamidronate therapy.

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Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management

Cited by 228 publications

References 32 publications

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

A General Agent-Based Model of Social Learning

Complications of pamidronate therapy in paediatric osteoporosis

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