Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

Vargas-Franco, Jorge William; Castañeda, Beatriz; Rédini, Françoise; Gomez, David F.; Heymann, Dominique; Lezot, Frédéric

doi:10.1002/jcp.26465

Cited by 42 publications

(35 citation statements)

References 109 publications

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“…Treatments that are currently in use to mitigate the effects of mechanical unloading are not without limitations and risks. Exercise in combination with drug treatments such as bisphosphonates have shown beneficial effects in astronauts 61,62 . However, in patients with osteoporosis, the use of bisphosphonates can increase the risk for atypical femoral fractures possibly due to suppressed bone turnover which may lead to cracks at the microscale and loss of mechanical strength 63,64 .…”

Section: Discussionmentioning

confidence: 99%

Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice

Steczina

Tahimic

Pendleton

et al. 2020

Sci Rep

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Spaceflight is a unique environment that includes at least two factors which can negatively impact skeletal health: microgravity and ionizing radiation. We have previously shown that a diet supplemented with dried plum powder (DP) prevented radiation-induced bone loss in mice. In this study, we investigated the capacity of the DP diet to prevent bone loss in mice following exposure to simulated spaceflight, combining microgravity (by hindlimb unloading) and radiation exposure. The DP diet was effective at preventing most decrements in bone micro-architectural and mechanical properties due to hindlimb unloading alone and simulated spaceflight. Furthermore, we show that the DP diet can protect osteoprogenitors from impairments resulting from simulated microgravity. Based on our findings, a dietary supplementation with DP could be an effective countermeasure against the skeletal deficits observed in astronauts during spaceflight.Alterations in the gravity vector and exposure to ionizing radiation can disrupt skeletal homeostasis in mice 1-3 . There are multiple stressors associated with spaceflight, including microgravity and radiation which are known to cause bone loss 4-6 . Decrements in bone mineral density (BMD) have been observed in astronauts from the Mir missions as well as missions to the International Space Station (ISS) 7-9 . While much research has focused on the detrimental effects of microgravity on skeletal tissue, less is known about the impact of spaceflight radiation. Crewed missions have, to this point, primarily remained within low-Earth orbit (LEO). While sources of ionizing space radiation within LEO include galactic cosmic radiation and charged particles from unpredictable solar particle events (SPE) 10,11 , the presence of the Earth's magnetosphere reduces exposure to ionizing space radiation. Missions beyond LEO pose the greatest risk of radiation exposure and is of significant concern for crew health 12-14 . Spaceflight-relevant radiation includes a mix of low-linear energy transfer (LET) species such as protons and helium ions as well as high-LET species such as iron 15,16 . Beyond LEO, for example, astronauts may be exposed to up to 0.7 Sv of ionizing radiation 12,15,17 during a multi-year mission to the Moon or Mars 14,15,18 .On Earth, bone homeostasis is effectively maintained by the controlled remodeling activity of bone-forming osteoblasts and bone-resorbing osteoclasts. However, exposure to low-LET radiation ( 137 Cs or X-ray, 1-2 Gy) leads to a transient increase in the number of osteoclasts, accompanied by an increase in trabecular separation (Tb.Sp) and decrease in trabecular thickness (Tb.Th), overall leading to a reduction in bone volume fraction (BV/TV) [19][20][21][22] . Together, this early increase in bone resorption and decrease in bone formation due to radiation exposure can result in a state of osteopenia, potentially leading to an increased risk of bone fracture 16,23,24 . A possible mechanism of action responsible for these changes in bone homeostasis is the generation o...

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Section: Discussionmentioning

confidence: 99%

Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice

Steczina

Tahimic

Pendleton

et al. 2020

Sci Rep

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“…While bisphosphonates are the principal drugs for the treatment of metabolic bone diseases, frequent adverse effects, such as atypical femoral fracture, osteonecrosis of the jaw, delayed dental eruption, and alterations to bone growth, have been described . Renal toxicity, osteonecrosis of the jaw, and low‐energy fractures have been reported in patients treated with bisphosphonates, including patients with multiple myeloma who were treated with bisphosphonoates .…”

Section: Mechanisms and Side Effects Of Osteoporosis Drugsmentioning

confidence: 99%

Novel insights into the complex architecture of osteoporosis molecular genetics

Saad

2019

Annals of the New York Academy of Sciences

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Osteoporosis is a prevalent osteodegenerative disease and silent killer linked to a decrease in bone mass and decline of bone microarchitecture, due to impaired bone matrix mineralization, raising the risk of fracture. Nevertheless, the process of bone matrix mineralization is still an unsolved mystery. Osteoporosis is a polygenic disorder associated with genetic and environmental risk factors; however, the majority of genes associated with osteoporosis remain largely unknown. Several signaling pathways regulate bone mass; therefore, dysregulation of a single signaling pathway leads to metabolic bone disease owing to high or low bone mass. Parathyroid hormone, core‐binding factor α‐1 (Cbfa1), Wnt/β‐catenin, the receptor activator of the nuclear factor kappa‐B (NF‐κB) ligand (RANKL), myostatin, and osteogenic exercise signaling pathways play pivotal roles in the regulation of bone mass. The myostatin signaling pathway increases bone resorption by activating the RANKL signaling pathway, whereas osteogenic exercise inhibits myostatin and sclerostin while inducing irisin that consequentially activates the Cbfa1 and Wnt/β‐catenin bone formation pathways. The aims of this review are to summarize what is known about osteoporosis‐related signaling pathways; define the role of these pathways in osteoporosis drug discovery; focus light on the link between bone, muscle, pancreas, and adipose integrative physiology and osteoporosis; and underline the emerging role of osteogenic exercise in the prevention of, and care for, osteoporosis, obesity, and diabetes.

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“…Current drugs for clinical use in treating osteoporosis, such as bisphosphonates, calcitonin, and estrogen, help maintain bone protein and mineral content and reduce fractures . However, serious side effects such as breast and endometrial cancer and hypercalcemia limit the use of these pharmacological drugs . Natural compounds with fewer side effects are more suitable than synthetic drugs for treating chronic diseases that require long‐term treatment .…”

Section: Introductionmentioning

confidence: 99%

Madecassoside inhibits estrogen deficiency‐induced osteoporosis by suppressing RANKL‐induced osteoclastogenesis

Wang

Yao

et al. 2018

J Cellular Molecular Medi

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Osteoporosis is the most common osteolytic disease characterized by excessive osteoclast formation and resultant bone loss, which afflicts millions of patients around the world. Madecassoside (MA), isolated from Centella asiatica, was reported to have anti‐inflammatory and antioxidant activities, but its role in osteoporosis treatment has not yet been confirmed. In our study, MA was found to have an inhibitory effect on the RANKL‐induced formation and function of OCs in a dose‐dependent manner without cytotoxicity. These effects were attributed to its ability to suppress the activity of two transcription factors (NFATc1 and c‐Fos) indispensable for osteoclast formation, followed by inhibition of the expression of bone resorption‐related genes and proteins (Acp5/TRAcP, CTSK, ATP6V0D2/V‐ATPase‐d2, and integrin β3). Furthermore, we examined the underlying mechanisms and found that MA represses osteoclastogenesis by blocking Ca2+ oscillations and the NF‐κB and MAPK pathways. In addition, the therapeutic effect of MA on preventing bone loss in vivo was further confirmed in an ovariectomized mouse model. Therefore, considering its ability to inhibit RANKL‐mediated osteoclastogenesis and the underlying mechanisms, MA might be a potential candidate for treating osteolytic bone diseases.

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Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

Cited by 42 publications

References 109 publications

Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice

Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice

Novel insights into the complex architecture of osteoporosis molecular genetics

Madecassoside inhibits estrogen deficiency‐induced osteoporosis by suppressing RANKL‐induced osteoclastogenesis

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