Trial Outcomes & Findings for DIVA Study - A Study of Different Regimens of Intravenous Administration of Bonviva (Ibandronate) in Women With Post-Menopausal Osteoporosis (NCT NCT00048074)

Last Updated: 2016-02-03

Results Overview

BMD was measured by a single dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine at the time of screening and at Month 12. The change in BMD was defined as the relative difference between the last individual measurement available at 12 months and Baseline, using the following formula: Relative change = 100 x (BMD at 1 year - BMD at Baseline) / (BMD at Baseline)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1395 participants

Primary outcome timeframe

Baseline and Month 12

Results posted on

2016-02-03

Participant Flow

A total of 1804 participants were screened for the study, from which 1395 participants were enrolled and randomized into treatment with ibandronate. The trial was conducted at 58 centers in 16 countries from June 2002 to May 2005.

Out of the 1395 participants who were randomized into the study, only 1382 participants received at least one dose of trial treatment and had at least one follow-up assessment as 4 participants did not have safety follow-up and 9 participants did not receive trial treatment.

Participant milestones

Participant milestones
Measure	Ibandronate 2.5mg Daily Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Overall Study STARTED	465	448	469
Overall Study COMPLETED	384	361	372
Overall Study NOT COMPLETED	81	87	97

Reasons for withdrawal

Reasons for withdrawal
Measure	Ibandronate 2.5mg Daily Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Overall Study Adverse Event	46	41	53
Overall Study Death	3	3	2
Overall Study Lost to Follow-up	2	6	6
Overall Study Withdrawal by Subject	28	30	35
Overall Study Protocol Violation	1	3	0
Overall Study Study participation was terminated	0	1	0
Overall Study Husband ill	0	1	0
Overall Study Poor compliance	0	1	0
Overall Study Out of station	0	1	1
Overall Study Social reasons	1	0	0

Baseline Characteristics

DIVA Study - A Study of Different Regimens of Intravenous Administration of Bonviva (Ibandronate) in Women With Post-Menopausal Osteoporosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ibandronate 2.5mg Daily n=465 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=448 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=469 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.	Total n=1382 Participants Total of all reporting groups
Age, Continuous	65.7 Years STANDARD_DEVIATION 6.08 • n=5 Participants	66.6 Years STANDARD_DEVIATION 6.26 • n=7 Participants	65.8 Years STANDARD_DEVIATION 6.30 • n=5 Participants	66.0 Years STANDARD_DEVIATION 6.22 • n=4 Participants
Sex: Female, Male Female	465 Participants n=5 Participants	448 Participants n=7 Participants	469 Participants n=5 Participants	1382 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Month 12

Population: Per protocol population: Participants who were randomized, received at least one dose of study medication and had at least one efficacy (BMD or serum CTX) follow-up data point and did not have any major violations of the protocol.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=368 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=359 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Relative Percent Change From Baseline in Mean Bone Mineral Density (BMD) of Lumbar Spine (L2-L4) at 12 Months	3.8199 Percent Change Standard Deviation 3.8576	5.0872 Percent Change Standard Deviation 3.8746	4.8188 Percent Change Standard Deviation 3.7613

SECONDARY outcome

Timeframe: Baseline and Month 24

BMD was measured by a single dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine at the time of screening and at Month 24. The change in BMD was defined as the relative difference between the last individual measurement available at 24 months and Baseline, using the following formula: Relative change = 100 x (BMD at 1 year - BMD at Baseline) / (BMD at Baseline)

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=334 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=320 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=334 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Relative Percent Change From Baseline in Mean BMD of Lumbar Spine (L2-L4) at 24 Months	4.8412 Percent Change Standard Deviation 4.8654	6.3999 Percent Change Standard Deviation 4.7392	6.2777 Percent Change Standard Deviation 5.0049

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

BMD was measured by a single dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine at screening, Month 12 and Month 24. The absolute change from Baseline in mean BMD of the lumbar spine (L2-L4) was defined as the difference between the last individual measurement available at Month 12 or Month 24 and Baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Absolute Change From Baseline in Mean BMD of Lumbar Spine (L2 - L4) at Month 12 and Month 24 Month 24, n= 334, 320, 334	0.036 Absolute Change (g/cm^2) Standard Deviation 0.0361	0.047 Absolute Change (g/cm^2) Standard Deviation 0.0347	0.046 Absolute Change (g/cm^2) Standard Deviation 0.0357
Absolute Change From Baseline in Mean BMD of Lumbar Spine (L2 - L4) at Month 12 and Month 24 Month 12, n= 368, 350, 359	0.028 Absolute Change (g/cm^2) Standard Deviation 0.0287	0.037 Absolute Change (g/cm^2) Standard Deviation 0.0282	0.035 Absolute Change (g/cm^2) Standard Deviation 0.0269

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

BMD was measured by a single DXA scan of the proximal femur at the time of screening, Month 12 and Month 24.The change in BMD of the proximal femur (total hip, trochanter, femoral neck) was defined as the relative difference between the last individual measurement available at Month 12 or Month 24and Baseline, using the following formula: Relative change = 100 x (BMD at 1 year/2year - BMD at Baseline) / (BMD at Baseline). BMD of fractured bones that could impact the scan area were not taken into account. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Relative Percent Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Trochanter, Month 24, n = 330, 316, 333	3.4669 Percent Change Standard Deviation 4.7241	5.0428 Percent Change Standard Deviation 4.4640	4.9165 Percent Change Standard Deviation 7.5057
Relative Percent Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Femoral neck, Month 12, n = 364, 343, 357	1.6129 Percent Change Standard Deviation 4.1050	1.9700 Percent Change Standard Deviation 3.5537	2.3055 Percent Change Standard Deviation 3.9283
Relative Percent Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Femoral neck, Month 24, n = 330, 316, 333	2.2457 Percent Change Standard Deviation 4.3015	2.7449 Percent Change Standard Deviation 4.1996	2.7849 Percent Change Standard Deviation 4.6723
Relative Percent Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Total hip, Month 12, n = 364, 343, 357	1.7857 Percent Change Standard Deviation 2.8171	2.5150 Percent Change Standard Deviation 2.6737	2.3604 Percent Change Standard Deviation 3.5156
Relative Percent Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Total hip , Month 24, n = 330, 316, 333	2.2011 Percent Change Standard Deviation 3.6997	3.3699 Percent Change Standard Deviation 2.9749	3.1279 Percent Change Standard Deviation 4.5422
Relative Percent Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Trochanter, Month 12, n = 364, 343, 357	2.9721 Percent Change Standard Deviation 4.1651	4.0275 Percent Change Standard Deviation 3.8890	3.8144 Percent Change Standard Deviation 6.0921

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

BMD was measured by a single DXA scan of the proximal femur at the time of screening, Month 12 and Month 24. The absolute change in BMD was defined as the difference between the last individual measurement available at Month 12 or Month 24 and Baseline. BMD of fractured bones that could impact the scan area were not taken into account. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Absolute Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Total hip, Month 24, n = 330, 316, 333	0.015 Absolute Change (g/cm^2) Standard Deviation 0.0259	0.025 Absolute Change (g/cm^2) Standard Deviation 0.0211	0.022 Absolute Change (g/cm^2) Standard Deviation 0.0278
Absolute Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Total hip, Month 12, n = 364, 343, 357	0.013 Absolute Change (g/cm^2) Standard Deviation 0.0202	0.018 Absolute Change (g/cm^2) Standard Deviation 0.0192	0.016 Absolute Change (g/cm^2) Standard Deviation 0.0213
Absolute Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Trochanter, Month 12, n = 364, 343, 357	0.016 Absolute Change (g/cm^2) Standard Deviation 0.0229	0.022 Absolute Change (g/cm^2) Standard Deviation 0.0209	0.020 Absolute Change (g/cm^2) Standard Deviation 0.0250
Absolute Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Trochanter, Month 24, n = 330, 316, 333	0.019 Absolute Change (g/cm^2) Standard Deviation 0.0256	0.029 Absolute Change (g/cm^2) Standard Deviation 0.0242	0.026 Absolute Change (g/cm^2) Standard Deviation 0.0322
Absolute Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Femoral neck , Month 12, n = 364, 343, 357	0.010 Absolute Change (g/cm^2) Standard Deviation 0.0243	0.013 Absolute Change (g/cm^2) Standard Deviation 0.0227	0.014 Absolute Change (g/cm^2) Standard Deviation 0.0240
Absolute Change From Baseline in BMD of Proximal Femur (Consisting of Total Hip, Trochanter, and Femoral Neck) at Month 12 and 24 Femoral neck , Month 24, n = 330, 316, 333	0.014 Absolute Change (g/cm^2) Standard Deviation 0.0258	0.018 Absolute Change (g/cm^2) Standard Deviation 0.0279	0.018 Absolute Change (g/cm^2) Standard Deviation 0.0278

SECONDARY outcome

Timeframe: Baseline, At Month 6, 12, and 24.

Serum CTX, a biochemical marker of bone resorption, was measured using the Elecsys s-CTX-I assay, an electrochemiluminescence immunoassay (ECLIA) technique. Samples for serum CTX measurements were collected from participants immediately prior to their IV dosing. Thus, the values reported here represent trough or residual values taken at the end of the 2 month or 3 month IV dosing interval. The change in serum CTX was defined as the relative difference between the last individual measurement available at Month 6 or Month 12 or Month 24 and Baseline, using the following formula: Relative change = 100 x (CTX at Month 6/Month 12/Month 24- CTX at Baseline) / (CTX at Baseline). Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Relative Change From Baseline in Serum C-telopeptide of Alpha-chain of Type I Collagen (CTX) at Month 6, 12, and 24 Month 6, n = 358, 342, 345	-54.715 Percent Change Standard Deviation 30.2820	-55.539 Percent Change Standard Deviation 42.6206	-51.196 Percent Change Standard Deviation 31.0579
Relative Change From Baseline in Serum C-telopeptide of Alpha-chain of Type I Collagen (CTX) at Month 6, 12, and 24 Month 12, n = 360, 342, 347	-54.387 Percent Change Standard Deviation 33.2810	-48.042 Percent Change Standard Deviation 95.3711	-49.873 Percent Change Standard Deviation 36.0415
Relative Change From Baseline in Serum C-telopeptide of Alpha-chain of Type I Collagen (CTX) at Month 6, 12, and 24 Month 24, n = 310, 301, 298	-51.549 Percent Change Standard Deviation 35.0888	-41.338 Percent Change Standard Deviation 76.8201	-44.325 Percent Change Standard Deviation 38.1338

SECONDARY outcome

Timeframe: Baseline, At Month 6, 12, and 24.

Serum CTX, a biochemical marker of bone resorption, was measured using the Elecsys s-CTX-I assay, an electrochemiluminescence immunoassay (ECLIA) technique. Samples for serum CTX measurements were collected from participants immediately prior to their IV dosing. Thus, the values reported here represent trough or residual values taken at the end of the 2 month or 3 month IV dosing interval. The absolute change from Baseline in serum CTX was defined as the difference between the last individual measurement available at Month 6 or Month 12 or Month 24 and Baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Absolute Change From Baseline in Serum CTX at Month 6, 12, and 24 Month 6, n = 358, 342, 345	-0.318 Absolute Change (ng/mL) Standard Deviation 0.2550	-0.322 Absolute Change (ng/mL) Standard Deviation 0.2015	-0.281 Absolute Change (ng/mL) Standard Deviation 0.2018
Absolute Change From Baseline in Serum CTX at Month 6, 12, and 24 Month 12, n = 360, 342, 347	-0.321 Absolute Change (ng/mL) Standard Deviation 0.2624	-0.318 Absolute Change (ng/mL) Standard Deviation 0.2239	-0.290 Absolute Change (ng/mL) Standard Deviation 0.2196
Absolute Change From Baseline in Serum CTX at Month 6, 12, and 24 Month 24, n = 310, 301, 298	-0.324 Absolute Change (ng/mL) Standard Deviation 0.2693	-0.285 Absolute Change (ng/mL) Standard Deviation 0.2092	-0.276 Absolute Change (ng/mL) Standard Deviation 0.2323

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean lumber spine (L2 - L4) BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Mean Lumbar Spine (L2 - L4) BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 368, 350, 359	85.1 Percentage of participants	92.3 Percentage of participants	91.6 Percentage of participants
Percentage of Participants With Mean Lumbar Spine (L2 - L4) BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 334, 320, 334	84.7 Percentage of participants	92.8 Percentage of participants	92.8 Percentage of participants

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean total hip BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Total Hip BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 364, 343, 357	74.5 Percentage of participants	86.0 Percentage of participants	82.6 Percentage of participants
Percentage of Participants With Total Hip BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 330, 316, 333	77.0 Percentage of participants	88.6 Percentage of participants	85.6 Percentage of participants

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean trochanter BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Trochanter BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 364, 343, 357	76.6 Percentage of participants	88.6 Percentage of participants	86.3 Percentage of participants
Percentage of Participants With Trochanter BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 330, 316, 333	80.0 Percentage of participants	92.1 Percentage of participants	88.6 Percentage of participants

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean femoral neck BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Femoral Neck BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 364, 343, 357	65.1 Percentage of participants	74.1 Percentage of participants	70.0 Percentage of participants
Percentage of Participants With Femoral Neck BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 330, 316, 333	67.6 Percentage of participants	77.5 Percentage of participants	76.6 Percentage of participants

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean total hip and mean lumbar spine BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Mean Total Hip and Lumbar Spine BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 363, 343, 355	66.9 Percentage of participants	80.5 Percentage of participants	76.3 Percentage of participants
Percentage of Participants With Mean Total Hip and Lumbar Spine BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 330, 314, 332	68.8 Percentage of participants	83.1 Percentage of participants	80.1 Percentage of participants

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean trochanter and lumbar spine BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Mean Trochanter and Lumbar Spine BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 363, 343, 355	68.0 Percentage of participants	83.4 Percentage of participants	79.7 Percentage of participants
Percentage of Participants With Mean Trochanter and Lumbar Spine BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 330, 314, 332	70.9 Percentage of participants	85.7 Percentage of participants	83.1 Percentage of participants

SECONDARY outcome

Timeframe: At Month 12 and 24

A participant is a responder if the mean femoral neck and lumbar spine BMD had remained the same or increased above baseline. Only participants with data available at particular timepoint were analyzed.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=375 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=350 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=364 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Percentage of Participants With Mean Femoral Neck and Lumbar Spine BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 12, n = 363, 343, 355	58.4 Percentage of participants	69.4 Percentage of participants	64.5 Percentage of participants
Percentage of Participants With Mean Femoral Neck and Lumbar Spine BMD Above or Equal to Baseline at Month 12 and 24 Above baseline, Month 24, n = 330, 314, 332	59.7 Percentage of participants	72.3 Percentage of participants	71.7 Percentage of participants

SECONDARY outcome

Timeframe: Approximately 2 years

Population: Safety Population: All participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.

An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=465 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=448 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=469 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Number of Participants Who Experienced Any Adverse Events (AEs) or Serious Adverse Events (SAEs) Any SAE	67 participants	73 participants	62 participants
Number of Participants Who Experienced Any Adverse Events (AEs) or Serious Adverse Events (SAEs) Any AE	408 participants	397 participants	400 participants

SECONDARY outcome

Timeframe: Approximately 2 years

Population: Safety Population: All participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point. Only participants with data available for the indicated laboratory abnormality were analyzed.

Marked laboratory test value abnormalities (high and low) are those which exceed the marked reference range (i.e., a reference range greater than the standard reference range) and which also represents a clinically relevant change from baseline of at least a designated amount. The indicated abnormal laboratory parameters (along with their marked reference range) are as follows: low and high Hematocrit (0.36 - 0.60 fraction), low and high hemoglobin (11.0 - 20.0 g/dL), low and high platelets (100 - 700 \* 10\^9/L), low and high white blood cell (WBC) (3.0 - 18.0 \* 10\^9/L), high alanine aminotransferase (ALAT) (0 - 60 U/L), high blood urea nitrogen (BUN) (0 - 14.3 mmol/L) , high creatinine (0 - 154 mmol/L), low albumin (27.0 - 48.0 g/L), low and high chloride (95 - 115 mmol/L), low potassium (3.0 - 6.0 mmol/L), low sodium (130 - 150 mmol/L), high calcium (2.00 - 2.90 mmol/L), low and high phosphate (0.75 - 1.60 mmol/L).

Outcome measures

Outcome measures
Measure	Ibandronate 2.5mg Daily n=465 Participants Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=448 Participants Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=469 Participants Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Number of Participants With Any Marked Abnormality in Laboratory Parameters Creatinine - High, n = 453, 434, 456	0 participants	2 participants	0 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Chloride - Low, n = 453, 433, 456	4 participants	3 participants	3 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Hematocrit - High, n = 453, 433, 456	0 participants	0 participants	1 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Hematocrit - low, n = 453, 433, 456	0 participants	2 participants	5 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Hemoglobin - High, n = 453, 433, 456	0 participants	1 participants	1 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Potassium - Low, n = 453, 433, 456	0 participants	1 participants	0 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Hemoglobin - Low n = 453, 433, 456	2 participants	5 participants	5 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Platelets - High, n = 452, 431, 455	0 participants	2 participants	1 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Platelets - Low, n = 452, 431, 455	2 participants	0 participants	1 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Sodium - Low, n = 453, 433, 456	0 participants	1 participants	1 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Calcium - High, n = 453, 434, 456	0 participants	1 participants	0 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Phosphate - High, n = 453, 434, 456	7 participants	4 participants	6 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Phosphate - Low, n = 453, 434, 456	6 participants	3 participants	2 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters WBC - High, n = 453, 433, 456	0 participants	1 participants	2 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters WBC - Low, n = 453, 433, 456	4 participants	4 participants	2 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters ALAT (SGPT) - High, n = 453, 434, 456	13 participants	12 participants	18 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters BUN - High, n = 453, 434, 456	1 participants	2 participants	0 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Albumin - Low, n = 453, 434, 456	0 participants	1 participants	0 participants
Number of Participants With Any Marked Abnormality in Laboratory Parameters Chloride - High, n = 453, 433, 456	1 participants	0 participants	0 participants

Adverse Events

Ibandronate 2.5mg Daily

Serious events: 67 serious events

Other events: 301 other events

Deaths: 0 deaths

Ibandronate 2mg q 2 mo IV

Serious events: 73 serious events

Other events: 316 other events

Deaths: 0 deaths

Ibandronate 3mg q 3 mo IV

Serious events: 62 serious events

Other events: 284 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Roche Trial Information Hotline

F. Hoffmann-La Roche AG

Phone: +41 616878333

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights
Publication restrictions are in place

Restriction type: OTHER

Measure	Ibandronate 2.5mg Daily n=465 participants at risk Participants received 2.5 milligrams (mg) of ibandronate orally daily and IV placebo injection at intervals of either 2 or 3 months for a total treatment period of 24 months.	Ibandronate 2mg q 2 mo IV n=448 participants at risk Participants received 2 mg of ibandronate intravenously (IV) every two months and placebo tablet daily for a total treatment period of 24 months.	Ibandronate 3mg q 3 mo IV n=469 participants at risk Participants received 3 mg of ibandronate IV every three months and placebo tablet daily for a total treatment period of 24 months.
Infections and infestations Nasopharyngitis	14.0% 65/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	14.7% 66/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	9.2% 43/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Infections and infestations Influenza	11.0% 51/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	9.6% 43/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	7.5% 35/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Infections and infestations Bronchitis	4.9% 23/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.2% 28/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.7% 22/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Infections and infestations Urinary tract infection	6.0% 28/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	5.4% 24/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	3.8% 18/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Infections and infestations Gastroenteritis	5.2% 24/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.2% 19/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	2.6% 12/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Musculoskeletal and connective tissue disorders Back pain	12.0% 56/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	13.8% 62/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	12.4% 58/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Musculoskeletal and connective tissue disorders Arthralgia	10.8% 50/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	12.3% 55/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	11.9% 56/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Musculoskeletal and connective tissue disorders Osteoarthritis	4.1% 19/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	5.8% 26/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.4% 30/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Musculoskeletal and connective tissue disorders Pain in extremity	3.4% 16/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.0% 27/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	3.8% 18/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Musculoskeletal and connective tissue disorders Bone pain	1.7% 8/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	5.1% 23/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	2.3% 11/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Gastrointestinal disorders Abdominal pain upper	7.1% 33/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	5.4% 24/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.2% 29/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Gastrointestinal disorders Dyspepsia	6.0% 28/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.2% 28/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.9% 23/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Gastrointestinal disorders Constipation	5.8% 27/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	7.4% 33/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	3.8% 18/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Gastrointestinal disorders Diarrhoea	3.9% 18/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	5.1% 23/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.3% 20/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Gastrointestinal disorders Nausea	5.4% 25/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.9% 22/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	2.8% 13/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Vascular disorders Hypertension	11.6% 54/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	9.8% 44/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	10.0% 47/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Metabolism and nutrition disorders Hypercholesterolaemia	6.9% 32/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.5% 29/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.1% 19/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.
Nervous system disorders Headache	4.5% 21/465 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	6.0% 27/448 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.	4.5% 21/469 • Approximately 2 years SAEs and non-serious AEs were reported for members of the safety population, comprised of participants who were randomized and had at least one dose of study drug, whether withdrawn prematurely or not, and who had at least one follow-up data point.