. 2019 May 30;76(19):3723–3744. doi: 10.1007/s00018-019-03162-w

Table 1.

List of miRNAs identified in osteoporosis and implicated in bone metastasis, and reported in clinical studies

Circulating miRNA	Up- or down-in cancer	References on osteoporosis	Effects on bone cells	Tumor	Effects in microenvironment and tumor cells	Number of patients Age range (Mean age)	Sample type	Reference on bone metastasis
Let-7b	Down	[40]	Let-7b down-regulation enhances matrix degradation and bone turnover	PC	Down-regulation of let-7b of PC patients is related to tumor progression	72 – (76.5)	Blood samples	[85]
Let-7b	Down	[40]		MM	Down-regulation of let-7b in blood and bone marrow of MM patients is related to tumor progression and osteolytic lesion formation	20 47–80 (64)	Blood samples	[120]
Let-7f	Down	[52]	Let-7b down-regulation inhibit OB differentiation	NSCLC	Down-regulation of let-7b in blood is related to tumor progression and associated with poor outcome	106 – –	Blood samples	[102]
miR-7	Down	[40]	Down-regulation promote OC differentiation	ESCC	miR-7 represent a non-invasive biomarker of diagnosis and predicting treatment responses to concurrent chemoradiation therapy	105 – –	Blood samples	[113]
miR-10b	Up	[37, 52]	miR-10b up-regulation inhibit OB differentiation	BC	Serum miR-10b level is significantly higher in patients with bone metastases than in patients without bone metastases or control subjects	23 – –	Primary and metastatic BC samples	[76]
						61 – –	Blood samples; primary BC samples	[63]
						122 26–77 52	Blood samples	[77]
				ESCC	Serum miR-10b level is up-regulated in serum e tumoral tissue of ESCC patients and its level in ESCC is revealed as independent prognostic marker of the overall survival rates of patients	195 – –	Blood samples; primary ESCC samples	[117]
miR-16	Up	[40, 56]	miR-16 down-regulation improve OB differentiation and inhibits OC differentiation	BC	Metastatic miR-16 up-regulation improve osteolytic lesion formation	38 – –	Blood samples; primary and metastatic BC samples	[59]
miR-16	Up	[40, 56]		BC	miR-16 level is related positively with tumor progression.	130 33–76 (56)	Blood samples	[60]
miR-21	Up	[31, 37, 46, 52]	miR-21 up-regulation inhibits OB and enhances OC differentiation	BC	Over-expression of miR-21 in the plasma of patients with BC is related to tumor progression Circulating miR-21 concentrations is able to distinguish patients with breast cancer from healthy females and further distinguish patients with distant metastases from those with locoregional disease	197 – –	Blood samples; primary BC samples	[64]
						15 – –	Blood samples; primary BC samples	[65]
						326 27–65 (46)	Blood samples; primary BC samples	[66]
						68 – –	Blood samples; primary BC samples	[61]
						102 – –	Blood samples, primary BC samples	[62]
						100 – –	Blood samples, primary BC samples	[69]
						61 – –	Blood samples; primary BC samples	[63]
						54 25–78 –	Blood samples; primary BC samples	[67]
						118 32.1–76.6 (45.6)	Blood samples	[68]
				PC	miR-21 level is correlated to the progression of tumor and metastasis formation and to the resistance to docetaxel-based chemotherapy	56 – (70.9)	Blood samples	[86]
					Up-regulation of serum miR-21 is related PC progression	25 51–82 (67)	Blood samples	[87]
					miR-21 up-regulation improve Tumor Growth, migration phenotype, bone colonization and metastasis formation	160 – –	Primary PC samples	[88]
				NSCLC	miR-21 up-regulation is related to malignant phenotype	221 – (66.3)	Blood samples	[98]
				NSCLC	miR-21 is up-regulated in serum of NSCLC and is correlated with tumor progression	63 36–83 –	Blood samples	[97]
				ESCC	miR-21 is up-regulated in serum of ESCC patient, permit discrimination between malign and benign disease, and response to treatment	99 27–83 (56.4)	Blood samples	[118]
miR-24	Up	[31, 46]	miR-24 up-regulation inhibits OB differentiation	BC	Up-regulation of serum miR-24 is related to the relapse of early BC and metastasis formation	133 37–84 (61.5)	Blood samples	[78]
				NSCLC	Serum miR-24 level is related NSCLC progression	400 – –	Blood samples	[108]
				ESCC	Serum miR-24 level is related ESCC progression	105 – –	Blood samples	[116]
miR-25	Up	[31]	miR-25 is up-regulated in osteoporotic patients	NSCLC	Up-regulation of serum miR-25 is related NSCLC progression	400 – –	Blood samples	[108]
				NSCLC	miR-25 level is high in NSCLC patients with metastasis respect to patient with non-metastatic tumors and healthy controls	438 – –	Blood samples	[100]
				ESCC	miR-25 is related to tumor progression and can considered as potential biomarkers for predicting the prognosis of ESCC patients	98 – (62)	Blood samples	[110]
						194 33–81 (61.4)	Blood samples	[111]
						99 27–83 (56.4)	Blood samples	[118]
miR-27a	Down	[55]	Up regulation inhibits OB differentiation	BC	Up-regulation of miR-27a is related to tumor progression	54 25–78 –	Blood samples	[67]
miR-29b	Down	[40, 45, 50]	miR-29b down-regulation inhibit OB differentiation	PC	Down-regulation of miR-29b is related to cancer cell migration and invasion of PC cells	27 63–88 (73.7)	Primary PC samples	[91]
				PC	Down-regulation of miR-29b is related to metastasis formation	187 – –	Primary PC samples	[92]
				MM	Up-regulation of miR-29b inhibits proliferation and induces apoptosis	9 – –	Primary MM patient samples	[122]
miR-30e	Down	[40]	miR-30e down-regulation inhibit OB differentiation	BC	miR-30e down-regulation is related to cancer cell invasion, osteomimicry, and bone destruction	109 – –	Primary BC cells	[79]
miR-30e	Down	[40]	miR-30e down-regulation inhibit OB differentiation	NSCLC	Down-regulation of miR-30e in blood is related to tumor progression and associated with poor outcome	106 – –	Blood samples	[102]
miR-34a	Down	[35]	miR-34a down-regulation inhibits OB and enhances OC differentiation	BC	miR-34a low expressions were associated with worse prognosis	84 > 50 –	Blood samples	[75]
				BC	miR-34a is moderately expressed in serum of BC patients, while is strongly downregulated in serum of patients with bone metastasis.	10 – –	Primary and metastatic BC samples	[74]
				PC	miR-34a is downregulated in Ras activated PC cells and is related to tumor growth and invasive phenotype.	170 – –	Primary and metastatic PC samples	[89]
				NSCLC	miR-34a high expression in plasma and tumor tissue were correlated with prolonged survival.	196 27–82 (58)	Blood samples; primary NSCLC samples	[99]
				ESCC	miR-34a down-expressions were associated with ESCC tumor progression and invasive phenotypes	111 – –	Primary ESCC samples	[114]
				ESCC	miR-34a down-expressions were associated with ESCC tumor progression	148 – –	Primary ESCC samples	[115]
miR-34c	Down	[40]	miR-34c down-regulation inhibits OB differentiation	BC	miR-34c low expressions were associated with worse prognosis	84 > 50 –	Blood samples	[75]
				BC	miR-34c is down-regulated in serum of BC patients	15 – –	Blood samples; primary BC samples	[65]
				NSCLC	miR-34c high expression in plasma and tumor tissue were both correlated with prolonged survival	196 27–82 (58)	Blood samples; primary NSCLC samples	[99]
miR-96	Up	[51]	miR-96 up-regulation inhibits OB differentiation	BC	Over-expression of miR-96 in the plasma of patients with BC is related to tumor progression	197 – –	Blood samples; primary BC samples	[64]
				PC	miR-96 levels were significantly higher in the blood of PC patients and is related to poor prognosis	26 > 55 –	Blood samples; primary PC samples	[93]
					Up-regulation of miR-96 induce tumor progression by suppression of ETV6 expression	69 – –	Primary PC samples	[94]
					Up-regulation of miR-96 induce tumor progression by inducing mTOR activities	170 – –	Primary PC samples	[95]
				NSCLC	High levels of circulating miR-96 in NSCLC patients is related to tumor progression	70 – –	Blood samples; primary NSCLC samples	[103]
				NSCLC		57 – –	Primary NSCLC samples	[104]
miR-100	Up	[31, 46]	miR-100 up-regulation inhibits OB differentiation	NSCLC	miR-100 levels were significantly higher in the blood of NSCLC patients with short survival	184 – –	Pleural effusion samples	[105]
miR-100	Up	[31, 46]	miR-100 up-regulation inhibits OB differentiation	ESCC	miR-100 is related to tumor progression and can considered as potential biomarkers for predicting the prognosis of ESCC patients	98 – (62)	Blood samples	[110]
miR-125b	Up	[30, 31, 46]	miR-125b up-regulation inhibits OB differentiation	BC	Over-expression of miR-125b in the plasma of patients with BC is related to tumor progression	197 – –	Blood samples; primary BC samples	[64]
					Over-expression of miR-21 in the plasma of patients with BC is related to tumor progression	118 32.1–76.6 (45.6)	Blood samples	[68]
					Higher circulating miR-125b level is correlated to more advanced ductal carcinoma of the breast and resistance for adjuvant chemotherapy	56 36–78 (55)	Blood samples	[70]
					Over-expression of miR-125b in the blood of patients with BC is related to tumor progression	61 – –	Blood samples; primary BC samples	[63]
				PC	High level of circulating miR-125b is related to aggressive phenotypes of PC cells	82 – –	Blood samples	[96]
				NSCLC	Circulating miR-125b level positively with cancer stage and associated with poor prognosis	193 – –	Blood samples	[106]
				NSCLC	Circulating miR-125b level is associated positively with cancer stage, tumor differentiation status and response to therapeutic treatment.	260 – (56.45)	Blood samples	[107]
miR-130	down	[40, 43]	miR-130 is down-regulated in osteoporotic patients	BC	Circulating miR-130 down-regulation is related to aggressive phenotype of BC	40 – –	Blood samples; Primary BC samples	[80]
miR-133	Up	[27, 32, 36, 37, 44]	miR-133 down-regulation inhibits OB and enhances OC differentiation	BC	miR-133 serum levels are significantly increased in BC patients	132 25–83 (53.8)	Blood samples; primary BC samples	[71]
miR-133	Up	[27, 32, 36, 37, 44]		ESCC	miR-133 serum levels are significantly increased in ESCC patients	290 52–70 (61.3)	Blood samples	[109]
miR-144	Down	[53]	miR-144 is down-regulated in osteoporotic patients	BC	miR-144 down-regulation is related to BC tumor progression	237 – –	Blood samples	[81]
miR-148	Up	[31, 41, 46]	miR-148 down-regulation inhibits OB and enhances OC differentiation	ESCC	miR-148 serum levels are significantly increased in ESCC patients	290 52–70 (61.3)	Blood samples	[109]
miR-152	Up	[40]	miR-152 is up-regulated in osteoporotic patients	PC	Up-regulation of serum miR-152 is related PC progression	25 51–82 (67)	Blood samples	[87]
miR-152	Up	[40]	miR-152 is up-regulated in osteoporotic patients	NSCLC	Up-regulation of serum miR-152 is related NSCLC progression	400 – –	Blood samples	[108]
miR-214	Up	[28, 52]	miR-214 up-regulation inhibit OB differentiation and promote OC differentiation	BC	miR-214 level is related to tumor progression and lytic bone lesion formations	134 30–82 (60)	Blood samples	[73]
				BC		37 – (53)	Primary BC samples	[72]
				PC	Increased expression of miR-214 are associated with tumor malignancy in PC patients through inhibition of PTEN expression	75 55–86 (72)	Blood samples	[90]
				NSCLC	miR-214 level is high in NSCLC patients with metastasis respect to patient with only primary tumours and healthy controls	438 – –	Blood samples	[100]
				MM	miR-214 level is related to tumor progression and lytic bone lesion formations	260 – –	Blood samples	[121]
miR-215	down	[40]	miR-25 is down-regulated in osteoporotic patients	BC	miR-215 level is related to BC tumor progression	75 – –	Blood samples	[82]
miR-215	down	[40]	miR-25 is down-regulated in osteoporotic patients	BC	miR-215 level is related to BC tumor progression	237 – –	Blood samples	[81]
miR-320	Up	[39, 40]	miR-320 up-regulation inhibit OB differentiation	NSCLC	Up-regulation of serum miR-320 is related NSCLC progression	400 – –	Blood samples	[108]
miR-335	Down	[40, 48]	miR-335 down-regulation inhibit OB and promote OC differentiation	BC	miR-335 down-regulation is related to BC tumor progression	68 – –	Blood samples; primary BC samples	[61]
miR-365	Down	[40]	miR-365 down-regulation promote OC differentiation	NSCLC	Circulating miR-365 level in NSCLC patients is correlated with poor differentiation tumor cells, advanced tumor stage and presence of metastasis, as well as short patients’ survival	100 30–88 60.18	Blood samples; primary NSCLC samples	[101]
miR-451	Up	[52]	miR-451 up-regulation inhibits OB differentiation	BC	High level of serum miR-451is associated to tumor grade	240 – –	Blood samples; primary BC samples	[83]
miR-451	Up	[52]	miR-451 up-regulation inhibits OB differentiation	ESCC	High level of serum miR-451 is associated to aggressive phenotype	65 – (62.77)	Blood samples; Primary ESCC samples	[112]
miR-483	Up	[39]	miR-483 up-regulation inhibits OB differentiation	NSCLC	miR-483 level is high in NSCLC patients with metastasis respect to patient with only primary tumours and healthy controls	438 – –	Blood samples	[100]