Effects of metformin on bone healing around titanium implants inserted in non‐diabetic rats

Bastos, Marta Ferreira; Serrão, Caroline Ribeiro; Miranda, Tamires Szeremeske; Cruz, Daniele Ferreira; Malta, Fernando de Souza; Duarte, Poliana Mendes

doi:10.1111/clr.12960

Cited by 9 publications

(6 citation statements)

References 32 publications

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“…In contrast, a lack of benefit has been seen in many other studies specifically examining bone regeneration or bone repair. In non‐diabetic Wistar rats, metformin had a detrimental effect on osseointegration around titanium bone implants . In non‐diabetic female rodents (either C57BL/6 ovariectomized mice or female Wistar rats), metformin treatment had no beneficial effect on fracture healing .…”

Section: Drugs and Bonementioning

confidence: 96%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Drugs and Bonementioning

confidence: 96%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…The anti‐diabetic agent and AMPK activator, metformin, has different effects in pathological and physiological states. ( 56–61 ) Although it is thought to improve skeletal parameters due to better glucose control in type 2 diabetics, it delays fracture healing in diabetic rats and suppresses markers of bone formation in type 2 diabetics with non‐alcoholic fatty liver disease. ( 57 ) Drugs used to treat cancer and transplant rejection (rapamycin and its analogs) interfere with mTORC1 signaling, but little is known about their non‐cancer–related skeletal effects.…”

Section: Discussionmentioning

confidence: 99%

Phosphate restriction impairs mTORC1 signaling leading to increased bone marrow adipose tissue and decreased bone in growing mice

Kobelski

Zhang

et al. 2020

Journal of Bone and Mineral Research

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Bone marrow stromal cells (BMSCs) are multipotent cells that differentiate into cells of the osteogenic and adipogenic lineage. A striking inverse relationship between bone marrow adipose tissue (BMAT) and bone volume is seen in several conditions, suggesting that differentiation of BMSCs into bone marrow adipocytes diverts cells from the osteogenic lineage, thereby compromising the structural and mechanical properties of bone. Phosphate restriction of growing mice acutely decreases bone formation, blocks osteoblast differentiation and increases BMAT. Studies performed to evaluate the cellular and molecular basis for the effects of acute phosphate restriction demonstrate that it acutely increases 5′ adenosine monophosphate–activated protein kinase (AMPK) phosphorylation and inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoblasts. This is accompanied by decreased expression of Wnt10b in BMSCs. Phosphate restriction also promotes expression of the key adipogenic transcription factors, peroxisome proliferator–activated receptor γ (PPARγ) and CCAAT‐enhancer binding protein α (CEBPα), in CXCL12 abundant reticular (CAR) cells, which represent undifferentiated BMSCs and are the main source of BMAT and osteoblasts in the adult murine skeleton. Consistent with this, lineage tracing studies reveal that the BMAT observed in phosphate‐restricted mice is of CAR cell origin. To determine whether circumventing the decrease in mTORC1 signaling in maturing osteoblasts attenuates the osteoblast and BMAT phenotype, phosphate‐restricted mice with OSX‐CreERT2–mediated haploinsufficiency of the mTORC1 inhibitor, TSC2, were generated. TSC2 haploinsufficiency in preosteoblasts/osteoblasts normalized bone volume and osteoblast number in phosphate‐restricted mice and attenuated the increase in BMAT observed. Thus, acute phosphate restriction leads to decreased bone and increases BMAT by impairing mTORC1 signaling in osterix‐expressing cells. © 2021 American Society for Bone and Mineral Research (ASBMR).

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“… Bastos et al. 81 2017 Wistar rats EG = 10 CG = 10 EG = MF CG = no treatment Tibia 40 mg/kg/day 30 days MF decreased bone-implant contact and bone area. The number of RANKL+ cells increased.…”

Section: Role Of Metformin In Osseointegration Of Implantsmentioning

confidence: 99%

“…Although the extent of the favorable effects has shown mixed results, the findings provide sufficient impetus for studies in human participants in the foreseeable future. 79 , 80 , 81 , 82 , 83 , 84 …”

Section: Role Of Metformin In Osseointegration Of Implantsmentioning

confidence: 99%