Non-steroidal anti-inflammatory drugs and bone healing in animal models—a systematic review and meta-analysis

Al-Waeli, Haider; Reboucas, Ana Paula; Mansour, Alaa; Morris, Martin; Tamimi, Faleh; Nicolau, Belinda

doi:10.1186/s13643-021-01690-w

Systematic Reviews

Table 1 Meta-analysis based on several subgroups showing the effect of NSAID administration on three-points mechanical bending measurements (maximum force, stiffness, and work to failure) of healing bones after fracture

From: Non-steroidal anti-inflammatory drugs and bone healing in animal models—a systematic review and meta-analysis

Subgroup	N	SZ NSAID	SZ C.	SMD	95% CI	P effect(adj. P value)	Q statistic	P within heterog.	I²%	P between heterog.
Maximum Force NSAID vs Control
Overall	94	995	594	− 0.58	[− 0.74, − 0.42]	0.000	206.89	< 0.001	55.04	–
Species
Rats	56	655	370	− 0.64	[− 0.85, − 0.43]	0.000(< 0.001)	117.18	< 0.001	53.06	0.336
Mice ^a	17	181	95	− 0.28	[− 0.68, 0.10]	0.154(0.205)	54.53	< 0.001	70.66
Rabbits	20	153	124	− 0.66	[− 1.02, − 0.31]	0.000(< 0.001)	32.9	0.025	42.26
Dogs	1	–	–	NA	NA	NA	–	–	NA
Sex
Female	22	261	148	− 0.61	[− 0.95, − 0.28]	0.000(< 0.001)	62.93	< 0.001	66.63	0.45
Male	63	667	377	− 0.52	[− 0.72, − 0.32]	0.000(< 0.001)	129.09	< 0.001	51.97
Not mentioned	9	67	70	− 0.87	[− 1.38, − 0.35]	0.000(< 0.001)	12.34	0.136	35.2
Age/weeks
< 8	3	24	21	0.26	[− 0.56, 1.09]	0.536(0.536)	0.249	0.883	0	0.023^a
8–16	39	471	270	− 0.40	[− 0.64, − 0.16]	0.001(0.002)	93.64	< 0.001	59.41
> 16	14	120	63	− 0.66	[− 1.10, − 0.21]	0.003(0.004)	14.514	0.339	10.43
Not mentioned	38	380	241	− 0.81	[− 1.05, − 0.56]	0.000(< 0.001)	80.64	< 0.001	54.12
Type of NSAID
NS-COX	53	528	349	− 0.55	[− 0.76, − 0.34]	0.000(< 0.001)	122.32	< 0.001	57.48	0.695
S-COX2	41	467	245	− 0.61	[− 0.86, − 0.37]	0.000(< 0.001)	83.79	< 0.001	52.26	0.695
Time point
< 21 days	20	214	123	− 0.62	[− 0.97, − 0.27]	0.001(0.002)	51.81	< 0.001	63.33	0.957
21–48 days	58	628	343	− 0.54	[− 0.75, − 0.33]	0.000(< 0.001)	124.99	< 0.001	54.39
> 48 days	15	129	104	− 0.65	[− 1.07, − 0.24]	0.002(0.003)	29.25	0.01	52.15
NM	1	–	–	NA	NA	NA	–	–	NA
Type of fractured bone
Femur	57	662	409	− 0.68	[− 0.88, − 0.48]	0.000(< 0.001)	120.03	< 0.001	53.34	0.01^a
Tibia^a	28	264	133	− 0.19	[− 0.49, 0.10]	0.2(0.2)	62.49	< 0.001	56.79
Fibula	4	27	11	− 0.69	[− 1.55, 0.16]	0.115(0.153)	5.67	0.128	47.15
Ulna	5	42	42	− 1.20	[− 1.86, − 0.55]	0.000(< 0.001)	1.03	0.906	0
Stiffness NSAID vs control
Overall	76	809	441	− 0.56	[− 0.76, − 0.37]	0.000	189.46	< 0.001	60.41	–
Species
Rats	50	582	318	− 0.57	[− 0.80, − 0.33]	0.000(< 0.001)	109.04	< 0.001	55.06	0.046^a
Mice ^a	14	145	59	− 0.07	[− 0.55, 0.40]	0.758(0.785)	55.63	< 0.001	76.63
Rabbits	11	76	58	− 1.06	[− 1.58, − 0.53]	0.000(< 0.001)	11.14	0.34	10.3
Dogs	1	–	–	NA	NA	NA	–	–	NA
Sex
Female	18	223	124	− 0.82	[− 1.21, − 0.44]	0.000(< 0.001)	40.88	0.001	58.41	0.022^a
Male	55	568	299	− 0.42	[− 0.64, − 0.19]	0.000(< 0.001)	133.42	< 0.001	59.52
Not mentioned	3	18	18	− 1.63	[− 2.64, − 0.62]	0.002(0.003)	0.78	0.675	0
Age/ weeks
< 8	3	24	21	0.00	[− 0.89, 0.91]	0.98(0.98)	0	1	0	0.047^a
8–16	30	373	193	− 0.39	[− 0.7, − 0.08]	0.01().02)	100.04	< 0.001	71.01
> 16^a	13	96	36	− 0.31	[− 0.82, 0.18]	0.21(0.28)	18.97	0.08	36.75
Not mentioned	30	316	188	− 0.88	[− 1.18, − 0.58]	0.000(< 0.001)	54.75	0.003	47.03
Type of NSAID
NS-COX	40	411	255	− 0.41	[− 0.67, − 0.15]	0.002(0.003)	78.83	< 0.001	50.52	0.091
S-COX2	36	398	186	0.75	[− 1.04, − 0.46]	0.000(< 0.001)	102.1	< 0.001	65.77	0.091
Time point
< 21 days	14	160	84	− 0.99	[− 1.43, − 0.54]	0.000(< 0.001)	21.48	0.06	39.49	0.085
21–48 days	51	560	292	− 0.42	[− 0.66, − 0.19]	0.000(< 0.001)	144.11	< 0.001	65.3
> 48 days	11	89	64	− 0.65	[− 1.16, − 0.13]	0.014(0.01)	12.11	0.27	17.46
Type of Fractured bone
Femur	46	531	299	− 0.59	[− 0.84, − 0.34]	0.000(<0.001)	100.78	< 0.001	55.34	0.458
Tibia	23	227	107	− 0.39	[− 0.76, − 0.02]	0.038(0.05)	78.93	< 0.001	72.12
Fibula	4	27	11	− 0.77	[− 1.71, 0.16]	0.107(0.1)	3.95	0.267	24.06
Ulna	3	24	24	− 1.16	[− 2.11, 0.20]	0.017(0.034)	0.32	0.848	0
Work to failure NSAID vs control
Overall	16	148	121	− 0.58	[− 0.95, − 0.20]	0.002	34.32	0.003	56.29	–
Species
Rats	12	117	92	− 0.52	[− 0.96, − 0.09]	0.017(0.034)	25.28	0.008	56.49	0.619
Rabbits	4	31	29	− 0.75	[− 1.51, 0.01]	0.054(0.054)	7.72	0.052	61.18	0.619
Sex
Female^a	6	65	66	− 0.09	[− 0.55, 0.36]	0.694(0.0694)	12.59	0.028	60.29	0.007^a
Male	10	83	55	− 0.94	[− 1.37, − 0.52]	0.000(< 0.001)	9.63	0.381	6.59	0.007^a
Age/weeks
< 8	0	–	–	–	–	–	–	–	–	0.267
8–16	3	24	24	− 1.16	[− 1.99, − 0.32]	0.006(0.007)	0.32	0.848	0
> 16	3	27	15	− 0.67	[− 1.54, 0.20]	0.131(0.131)	7.42	0.024	73.07
Not mentioned	10	97	82	− 0.38	[− 0.83, 0.05]	0.089(0.118)	19.88	0.019	54.73
Type of NSAID
NS-COX	11	411	255	− 0.58	[− 1.05, − 0.11]	0.015(0.03)	26.52	0.003	62.30	0.99
S-COX2^a	5	398	186	− 0.58	[− 1.26, 0.09]	0.092(0.092)	7.72	0.102	48.18	0.99
Time point
< 21 days	1	–	–	NA	NA	NA	–	–	NA	0.03^a
21–48 days	12	102	75	− 0.71	[− 1.10, − 0.32]	0.000(< 0.001)	19.54	0.052	43.73
> 48 days	3	35	35	− 0.59	[− 1.26, 0.07]	0.083().12)	2.174	0.33	8.00
Type of fractured bone
Femur^a	10	97	82	− 0.38	[− 0.83, 0.05]	0.089(0.12)	19.88	0.019	54.73	0.267
Tibia	3	27	15	− 0.67	[− 1.54, 0.20]	0.131(0.131)	7.42	0.024	73.07
Ulna	3	24	24	− 1.16	[− 1.99, − 0.32]	0.006(0.018)	0.32	0.848	0

N number of comparisons in analysis, SZ NSAID number of animals in non-steroidal anti-inflammatory drug (NSAID) group, SZ C. number of animals in control group, SMD standardized means of differences (Hedges’ g), CI confidence interval, NS-COX non-selective cyclooxygenase inhibitor, S-COX2 selective cyclooxygenase 2 inhibitor, NA not analyzed because of insufficient data, adj.P value adjusted P value through Holm-Bonferroni correction
^aNeed to be explained—more details in Tables S5–S22 (supplementary information file)

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