Alendronate/Vitamin D for attenuating bone mineral density loss during antiretroviral initiation: a pilot randomized controlled trial

Figures & data

Table 1 Demographic and clinical characteristics of participants at baseline^a

Variable	All (n = 29)	SOC (n = 9)	CTA (n = 10)	DTA (n = 10)
Age, years (range)	33.2 (26.4, 42.0)	41.8 (24.1, 44.0)	29.7 (26.4, 37.0)	34.0 (31.1, 35.8)
Male sex, n (%)	28 (96.6)	9 (100.0)	10 (100.0)	9 (90.0)
Race, n (%)
Black	8 (27.6)	1 (11.1)	2 (20.0)	5 (50.0)
White	13 (44.8)	5 (55.6)	4 (40.0)	4 (40.0)
Other	8 (27.6)	3 (33.3)	4 (40.0)	1 (10.0)
Born in Canada	13 (44.8)	6 (66.7)	4 (40.0)	3 (30.0)
ART regimen initiated, n (%)
TDF/FTC/ELV/c	21 (72.4)	7 (77.8)	7 (70.0)	7 (70.0)
ABC/3TC/DTG	8 (27.6)	2 (22.2)	3 (30.0)	3 (30.0)
Risk factors for HIV acquisition, n (%)^b
Homosexual contact	25 (86.2)	8 (88.9)	9 (90.0)	8 (80.0)
Heterosexual contact	6 (20.7)	2 (22.2)	3 (30.0)	1 (10.0)
Injection drug use	1 (3.4)	1 (11.1)	0 (0.0)	0 (0.0)
Blood product	1 (3.4)	0 (0.0)	0 (0.0)	1 (10.0)
Endemic country	1 (3.4)	0 (0.0)	0 (0.0)	1 (10.0)
Injection (piercing, tattooing)	1 (3.4)	0 (0.0)	1 (10.0)	0 (0.0)
Baseline CD4 count, cells/mm^3	388 (303, 525)	374 (301, 660)	402 (297, 476)	481 (319, 562)
Nadir CD4 count, cells/mm^3	320 (281, 457)	336 (298, 489)	311 (239, 434)	362 (295, 490)
Baseline CD4 percent	24.0 (18.0, 29.0)	24.0 (16.0, 29.0)	19.0 (17.0, 27.0)	26.0 (20.0, 29.0)
Nadir CD4 percent	26.0 (17.0, 28.0)	22.0 (16.0, 29.0)	18.9 (17.0, 26.0)	26.0 (21.9, 27.2)
Viral load, log10 copies per mL	4.45 (2.26, 4.84)	4.25 (2.15, 4.47)	4.44 (2.48, 5.32)	4.57 (2.49, 4.89)
Years since HIV diagnosis	0.7 (0.3, 2.8)	0.8 (0.4, 2.8)	0.6 (0.2, 0.7)	1.4 (0.3, 2.9)
Any osteoporosis risk medications^c
Never	26 (89.7)	8 (88.9)	10 (100.0)	8 (80.0)
Current	3 (10.3)	1 (11.1)	0 (0.0)	2 (20.0)
Other osteoporosis risk factors, n (%)^b
Parental hip fracture	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Current smoking	6 (20.7)	3 (33.3)	1 (10.0)	2 (20.0)
Glucocorticoids	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Rheumatoid arthritis	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Secondary osteoporosis	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Alcohol 3 or more units/day	2 (6.9)	1 (11.1)	1 (10.0)	0 (0.0)
Any of the above	7 (24.1)	4 (44.4)	1 (10.0)	2 (20.0)
10-year probability of major osteoporotic fracture (%)^d	2.2 (1.2, 2.6)	2.3 (1.5, 2.5)	1.2 (1.2, 2.6)	2.3 (1.4, 3.4)
10-year probability of hip fracture (%)^d	0.1 (0.0, 0.1)	0.1 (0.0, 0.1)	0.1 (0.0, 0.1)	0.1 (0.1, 0.1)
Body mass index (kg/m^2)	25.7 (23.6, 26.8)	25.7 (24.4, 26.6)	24.4 (22.4, 26.5)	26.2 (24.8, 27.7)
Grip strength, average of three measures (kg)^e	34.5 (28.0, 39.5)	35.3 (29.0, 38.0)	32.8 (28.7, 40.0)	35.3 (27.3, 40.0)
Participation in regular weight-bearing exercise, n (%)	10 (34.5)	5 (55.6)	1 (10.0)	4 (40.0)
Total physical activity (MET-minutes/week)^f	4518 (1497, 8267)	5673 (3528, 6558)	3501 (1410, 7818)	7758 (1497, 8267)
Level of physical activity, n (%)
Unknown	3	1	1	1
Low	2 (7.7)	0 (0.0)	1 (11.1)	1 (11.1)
Moderate	8 (30.8)	1 (12.5)	4 (44.4)	3 (33.3)
High	16 (61.5)	7 (87.5)	4 (44.4)	5 (55.6)

^a Values are median (IQR) and frequency (%) unless otherwise noted. SOC = Standard of care, CTA = Concomitant treatment arm, DTA = Delayed treatment arm.

^b Multiple values possible for each participant.

^c Includes inhaled fluticasone, inhaled fluticasone/salmeterol, escitalopram.

^d Based on the FRAX score validated for Canadian populations, with age assigned a value of 40 for those aged under 40 years.

^e Missing for one participant.

^f Values available for 6, 8 and 9 participants in the three arms respectively.

Figure 1 Mean BMD over time by study group and anatomic site. Note: The sample size varied slightly across time points, with 27, 24 and 23 participants at baseline, week 24 and week 48 respectively. Thus, there may be small discrepancies between the BMD trend exhibited in the figure and the mean changes shown in Table 2, which was computed based on participants with both baseline and follow-up data.

Table 2 Baseline mean (SD) BMD values and mean (SD) change from baseline in BMD at 24 and 48 weeks, by study arm^a

	All	Control	Concomitant	Delayed	Combined active	Control & delayed combined
Lumbar Spine
Baseline (g/cm^2)	1.038 (0.112)	1.047 (0.080)	1.012 (0.153)	1.057 (0.086)	1.034 (0.123)	1.053 (0.081)
Change at week 24 (g/cm^2)	0.001 (0.027)	−0.004 (0.012)	0.016 (0.026)	−0.013 (0.028)	–	−0.009 (0.022)
Change at week 48 (g/cm^2)	0.016 (0.027)	0.001 (0.010)	0.014 (0.033)	0.032 (0.019)	0.021 (0.029)	–
Change at week 24 (%)	0.11 (2.64)	−0.32 (1.10)	1.59 (2.75)	−1.19 (2.74)	–	−0.81 (2.17)
Change at week 48 (%)	1.45 (2.37)	0.02 (1.00)	1.22 (2.78)	3.00 (1.82)	1.95 (2.53)	–
Left hip femoral neck
Baseline (g/cm^2)	0.923 (0.127)	0.916 (0.140)	0.931 (0.149)	0.921 (0.106)	0.926 (0.126)	0.919 (0.117)
Change at week 24 (g/cm^2)	−0.006 (0.035)	−0.011 (0.050)	0.006 (0.029)	−0.014 (0.027)	–	−0.013 (0.037)
Change at week 48 (g/cm^2)	0.000 (0.035)	−0.007 (0.051)	−0.001 (0.034)	0.008 (0.023)	0.003 (0.030)	–
Change at week 24 (%)	−0.46 (3.53)	−1.06 (4.90)	0.79 (3.07)	−1.39 (2.66)	–	−1.24 (3.66)
Change at week 48 (%)	0.12 (3.74)	−0.61 (5.01)	0.01 (3.92)	0.91 (2.49)	0.38 (3.34)	–
Total left hip
Baseline (g/cm^2)	1.073 (0.112)	1.108 (0.123)	1.060 (0.130)	1.062 (0.088)	1.061 (0.108)	1.081 (0.103)
Change at week 24 (g/cm^2)	−0.011 (0.025)	−0.020 (0.035)	−0.005 (0.017)	−0.011 (0.024)	–	−0.015 (0.029)
Change at week 48 (g/cm^2)	−0.014 (0.036)	−0.036 (0.029)	−0.009 (0.043)	−0.002 (0.025)	−0.006 (0.036)	–
Change at week 24 (%)	−0.97 (2.25)	−1.66 (3.03)	−0.46 (1.69)	−1.00 (2.21)	–	−1.28 (2.53)
Change at week 48 (%)	−1.25 (3.41)	−3.16 (2.46)	−0.85 (4.25)	−0.18 (2.30)	−0.57 (3.50)	–

^a The sample size varied slightly across time points as follows: there were 27 participants at baseline (7 SOC, 10 CTA and 10 DTA), 26 participants at week 24 (7 SOC, 10 CTA and 9 DTA) and 23 participants at week 48 (6 SOC, 10 CTA and 7 DTA).

Table 3 Linear mixed regression results showing differences in BMD at weeks 24 and 48 between study arms

		Difference in BMD (95% CI)
Variable	Comparison	Week 24	P	Week 48	P
Lumbar Spine (g/cm^2)	CTA vs. SOC	0.020 (−0.004, 0.045)	0.105	0.017 (−0.009, 0.042)	0.189
	CTA vs. SOC & DTA	0.025 (0.005, 0.045)	0.017	–
	DTA vs. SOC	−0.009 (−0.034, 0.016)	0.456	0.037 (0.010, 0.063)	0.008
	DTA vs. CTA	−0.029 (−0.052, −0.006)	0.014	0.020 (−0.004, 0.044)	0.098
	Combined CTA & DTA vs. SOC	–		0.025 (0.002, 0.048)	0.033
Lumbar Spine (% change)	CTA vs. SOC	1.8 (−0.6, 4.2)	0.128	1.4 (−1.1, 3.8)	0.272
	CTA vs. SOC & DTA	2.3 (0.3, 4.2)	0.025	–
	DTA vs. SOC	−0.9 (−3.3, 1.6)	0.478	3.5 (1.0, 6.1)	0.008
	DTA vs. CTA	−2.7 (−4.9, −0.4)	0.021	2.2 (−0.2, 4.5)	0.066
	Combined CTA & DTA vs. SOC	–		2.3 (0.0, 4.5)	0.047
Left hip femoral neck (g/cm^2)	CTA vs. SOC	0.018 (−0.017, 0.053)	0.297	0.009 (−0.026, 0.045)	0.594
	CTA vs. SOC & DTA	0.019 (−0.009, 0.047)	0.182	–
	DTA vs. SOC	−0.002 (−0.037, 0.034)	0.918	0.015 (−0.022, 0.052)	0.414
	DTA vs. CTA	−0.020 (−0.052, 0.012)	0.220	0.006 (−0.027, 0.039)	0.726
	Combined CTA & DTA vs. SOC	–		0.012 (−0.021, 0.044)	0.464
Left hip femoral neck (% change)	CTA vs. SOC	2.0 (−1.6, 5.6)	0.267	1.0 (−2.7, 4.7)	0.591
	CTA vs. SOC & DTA	2.1 (−0.9, 5.0)	0.159	–
	DTA vs. SOC	−0.2 (−3.9, 3.5)	0.928	1.5 (−2.4, 5.5)	0.428
	DTA vs. CTA	−2.2 (−5.5, 1.2)	0.198	0.6 (−2.9, 4.0)	0.748
	Combined CTA & DTA vs. SOC	–		1.2 (−2.2, 4.6)	0.469
Total left hip (g/cm^2)	CTA vs. SOC	0.011 (−0.019, 0.042)	0.451	0.025 (−0.006, 0.056)	0.112
	CTA vs. SOC & DTA	0.008 (−0.017, 0.033)	0.507	–
	DTA vs. SOC	0.006 (−0.025, 0.037)	0.688	0.032 (−0.001, 0.064)	0.054
	DTA vs. CTA	−0.005 (−0.033, 0.023)	0.704	0.007 (−0.022, 0.036)	0.633
	Combined CTA & DTA vs. SOC	–		0.028 (−0.000, 0.056)	0.054
Total left hip (% change)	CTA vs. SOC	0.9 (−2.0, 3.8)	0.521	2.2 (−0.8, 5.1)	0.140
	CTA vs. SOC & DTA	0.7 (−1.7, 3.0)	0.560	–
	DTA vs. SOC	0.5 (−2.5, 3.4)	0.754	2.8 (−0.3, 5.9)	0.071
	DTA vs. CTA	−0.46 (−3.1, 2.2)	0.724	0.6 (−2.1, 3.4)	0.645
	Combined CTA & DTA vs. SOC	–		2.4 (−0.2, 5.1)	0.072

Table 4 Estimated sample size requirements for a 1:1 randomized controlled trial of alendronate/vitamin D during antiretroviral initiation (for α = 0.05 and 80% power)

Detectable difference between study arms in % change in BMD at 48 weeks	Within-group standard deviation in % change in BMD at 48 weeks	N per arm	N total accounting for 10% loss-to-follow-up
1.0	2.5	99	220
1.5	2.5	45	100
2.0	2.5	26	58
1.0	3	142	316
1.5	3	64	142
2.0	3	36	80
1.0	3.5	193	429
1.5	3.5	86	191
2.0	3.5	49	109
1.0	4	252	560
1.5	4	113	251
2.0	4	64	142
1.0	4.5	319	709
1.5	4.5	142	316
2.0	4.5	80	178
1.0	5	393	873
1.5	5	175	389
2.0	5	99	220