Table 1.

Studies included in this review and their details.

Type of Study	Investigated Subject	Investigated Material	Dose/Concentration	Results/Outcome	Comment	References
In vitro	CFU-E; BFU-E	C. sinensis	100, 150, 200 µg/mL	Increases the number of erythroid cells CFU-E and BFU-E	Content of cordycepin not determined	[24]
In vivo	Mice	C. sinensis	50, 100, 150, 200, 250, 300 mg/kg/day; intraperitoneal injection for 5 days	Stimulates erythropoiesis; increases the number of CFU-E and BFU-E in mouse bone marrow	Content of cordycepin not determined
In vitro	BMCs	C. militaris water extract	Up to 250 µg/mL	Induced maturation of murine BMCs	Content of cordycepin not determined	[25]
In vitro	BMCs: BMMSCs; BMHSCs	C. sinensis water extract	500 µg/mL	Stimulate the proliferation of BMCs; protection of BMCs from radiation cytotoxicity	Content of cordycepin not determined	[26]
In vivo	Mice	C. sinensis water extract	50 mg/kg/day; oral administration for 1 week	Protection of mice bone marrow after TBI; increase a survival of mice receiving TBI	Content of cordycepin not determined
In vitro	Mouse BMCs and monocyte macrophage RAW 264.7 cells	C. sinensis water extract	10, 50, 100 µg/mL	Inhibition of RANKL-induced osteoclast differentiation via NF-κB pathway	Content of cordycepin not determined	[27]
In vitro	BMMSCs; BMHSCs	C. sinensis extract	500 µg/mL	Stimulate the differentiation of BMCs	Content of cordycepin not determined	[28]
In vivo	Mice with leukopenia induced by paclitaxel	C. sinensis extract	50 mg/kg/day for 3 weeks	Enhancement recovery of mice from leukopenia induced by paclitaxel	Content of cordycepin not determined
In vivo	OVX osteopenic rats	C. sinensis rich in strontium	10 mL a mixture of C. sinensis rich in strontium; oral administration for 8 weeks	Decreases bone resorption, increases bone formation; increase the estradiol level	Content of cordycepin not determined	[29]
In vivo	OVX osteopenic rats	C. sinensis rich in strontium	10 mL a mixture of C. sinensis rich in strontium; oral administration for 8 weeks	Decrease of ALP and TRAP activity; decrease of CTX and IFN-γ level; increase the OC and estradiol level	Content of cordycepin not determined	[30]
In vivo	Rats	C. sinensis extract	100, 300, 500 mg/kg/day; oral administration for 8 weeks	Increase the bone mineral density; prevent disuse-induced bone loss	Content of cordycepin 5.27 µg/g	[31]
In vivo	Model diabetic osteopenic rats	Cordymin from C. sinensis	20, 50, 100 mg/kg/day; intraperitoneal injection for 5 weeks	Decrease of ALP and TRAP activity	—	[32]
In vivo	OVX rats	Isoflavones from C. sinensis	20, 50, 100 mg; oral administration for 8 weeks	Prevent of bone loss induced by estrogen deficiency; decrease of urinary Ca excretion; decrease of ALP and TRAP activity; decrease of CTX and IFN-γ level; increase the OC and estradiol level	Performed a histological examination of bone	[33]
In vivo	Broiler chicken	Fermentation products of C. militaris	1–4 g fermentation products of C. militaris per 1 kg of feed	Increased calcium content in tibia	Content of cordycepin 5.09 mg/g. High dose at 4 g/kg of fermentation products of C. militaris had a negative impact on bone mineralization	[34]
In vivo	Rats with IMO	Cordycepin	5, 10, 20 mg/kg; oral administration two times daily for 3 weeks	Prevent of bone loss; decrease of CTX, MDA, IL-1β, TNF-α level in the serum; increase the OC level	Performed a histological examination of liver, not bone	[35]
In vitro	ADMSCs	Cordycepin	10–40 µg/mL	Low concentration of cordycepin 10 µg/mL promoted osteogenic differentiation	High concentration of cordycepin 20–40 µg/mL induce cell death	[36]
In vitro	Murine mesenchymal stem cells	Cordycepin	10, 20, 50 µg/mL	Decrease of ALP and TRAP activity	—	[37]
In vivo	OVX osteopenic rats	Cordycepin	5, 10, 20 mg/kg; oral administration two times daily for 3 weeks	Prevention of bone loss; increase the OC level; decrease the CTX level	Performed a histological examination of bone
In vitro	BMMSCs	Cordycepin from C. militaris	0.1, 0.2, 0.5, 1, 2 mM; 1, 5, 10, 20, 40, 80 μg/mL	Promoted osteogenic differentiation; decrease of ALP and TRAP activity	—	[38]
In vivo	OVX mice	Cordycepin from C. militaris	1, 5, 10 and 20 mg/kg; intraperitoneal injection for 8 weeks	Increase of calcium content	Did not perform a histological examination of bone
In vitro	Mouse monocyte macrophage RAW 264.7 cells	C. militaris and cordycepin	1, 10 µg/mL	Inhibition of osteoclast differentiation	—	[39]
In vivo	Mouse model of lipopolysaccharide-mediated bone loss	C. militaris (content cordycepin)	100 µg/g; oral administration for 8 days	Prevention of bone loss	Did not perform a histological examination of bone; performed a micro-CT analysis
In vitro	Mouse monocyte macrophage RAW 264.7 cells and BMMs	Cordycepin	0.01, 0.05, 0.1, 0.5, 1, 5, 10 μg/mL	Inhibition of RANKL-induced osteoclastogenesis	Inhbitory effects of cordycepin started at 0.1 μg/mL; concentration of cordycepin above to 5 μg/mL; cytotoxic effect started at concentration of 5 µg/mL	[40]
In vivo	OVX mice	Cordycepin	10 mg/kg/day; Oral administration for 4 weeks	Prevention of bone loss	Performed a histological analysis; performed a BMD analysis
In vitro	HBMSCs	Cordycepin	0.1, 1, 10 μg/mL	Decrease of ALP activity	Even a high concentration at 10 μg/mL not suppress a proliferation of HBMSCs	[41]
In vivo	Rats model of alcohol-induced ONFH	Cordycepin	10 mg/kg/day; intraperitoneal injection for 6 weeks	Cordycepin prevent on alcohol-induced ONFH	Performed a micro-CT analysis
In vitro	Murine MC3T3-E1 and RAW264.7 cells	Cordycepin	0.5, 1 µM	Inhibition of RANKL-induced osteoclast differentiation	Even a high concentration at 5 µM provide no cytotoxic effect	[42]
In vitro	BMMSCs	Cordycepin	10 µg/mL	Promotes osteogenesis	—	[43]
In vivo	Rat model of closed femur fracture	Cordycepin	10 mg/kg/day	Accelerate a fracture healing	Performed a histological analysis
In vitro	Osteosarcoma cells and osteoblast cells	Cordycepin	100, 200, and 400 µM	Inhibition of proliferation osteosarcoma cells; induce of osteosarcoma cell apoptosis	—	[44]
In vivo	Mice	Cordycepin	40 mg/kg/day; intraperitoneal injection for 32 days	Inhibited osteosarcoma cell invasion	—
In vitro	Dental pulp stem cells	Cordycepin	0.5, 1, 2.5, 5, 10, 25, 50 µM	Increased the expression of RUNX2, COL1A1, OSX, OCN	—	[45]
In vitro	Dental pulp stem cells	Cordycepin	1, 2.5, 5, 10, 25, 50 µM	Increased the migration of dental pulp stem; increase the number of stem cells	Concentration above at 10 µM resulted an cytotoxic effects	[46]
In vivo	Mice with myelosuppression induced by cyclophosphamide	Nucleosides and amino acids from C. sinensis (natural and artificially-cultivated)	0.48–1.78 (contents ratio of artificially-cultivated versus natural C. sinensis)	Protection against myelosuppression induced by cyclophosphamide	Content of cordycepin not determined	[47]

Colony-forming unit—erythroid (CFU-E); Burst-forming unit—Erythroid (BFU-E); Murine bone marrow cells (BMCs); Bone marrow mesenchymal stem cells (BMMSCs); Bone marrow hematopoietic stem cells (BMHSCs); Total body irradiation (TBI); Receptor Activator for Nuclear Factor κB Ligand (RANKL); Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); Ovariectomized (OVX); Alkaline phosphatase (ALP); Tartrate-resistant acid phosphatase (TRAP); Cross-linked carboxy terminal telopeptide of type I collagen (CTX); Interferon gamma (IFN-γ); Osteocalcin (OC); Inflammation-induced osteoporosis (IMO); Malondialdehyde (MDA); Interleukin 1 beta (IL-1β); Tumor necrosis factor alpha (TNF-α); Human adipose-derived mesenchymal stem cells (ADMSCs); Mesenchymal Stem Cells (MSCs); Bone marrow macrophages (BMMs); Human bone mesenchymal stem cells (HBMSCs); Bone mineral density (BMD); Osteonecrosis of the femoral head (ONFH); Runt-related transcription factor 2 (RUNX2); Type I collagen alpha 1 (COL1A1); Osterix (OSX); Bone gamma carboxyglutamic acid-containing protein/osteocalcin gens (OCN).