Fracture risk associated with continuation versus discontinuation of bisphosphonates after 5 years of therapy in patients with primary osteoporosis: a systematic review and meta-analysis

Figures & data

Figure 1 Flow diagram of study selection.

Table 1 Characteristics of included studies

Study	Participants	Intervention	Outcomes	Methodological quality	Notes
Black et al^Citation17	1099 postmenopausal women from the US, originally with BMD ≤ 0.68 g/cm^2, who received alendronate	Alendronate 5 mg/day (n = 329) or 10 mg/day (n = 333) vs placebo (n = 437) for 5 years	Change in BMD at hip and other sites Changes in bone turnover markers Fracture incidence^a Outcomes measured at 5-year follow-up	AS adequately generated AC not clear Blinding: patients, physicians, data collectors, and outcome assessors Incomplete data adequately addressed No selective outcome reporting, or other threats to validity	Funded by Merck and Co. (makers of alendronate, the study drug) Merck involved with study design, editorial input, and approval of final manuscript Not all participants had “osteoporosis” by WHO definition, inclusion criterion was BMD ≤ 0.68 g/cm^2
	5 mg/day for 2 years and then 10 mg/day for a total mean duration of therapy of 5 years’ treatment during the Fracture Intervention Trial
Bone et al^Citation19	804 postmenopausal women from multiple countries with BMD T-scores <–2.5 underwent initial randomization; 247 included in the year 8–10 extension study (used for this review)	Alendronate 5 mg/day (n = 78) vs 10 mg/day (n = 86) for 10 yrs vs 20 mg/day for 2 years then 5 mg/day for 3 years then placebo for 5 years (n = 83)	Change in BMD at lumbar spine and other sites Changes in bone turnover markers Morphometric and clinical vertebral fracture incidence^b Height change Safety Outcomes measured at either 2- or 5-year follow-up	AS and AC not clear “Double blinded”, also data assessors blinded Incomplete data not adequately addressed All outcomes not fully reported No other threats to validity	Funded by Merck Research Laboratories (makers of alendronate, the study drug) First author with honorariums and grant support from Merck
Miller et al^Citation18	97 postmenopausal women from the US with a history of fragility fracture completed 7 years of follow-up with at least 5 years of etidronate therapy	Continued cyclical etidronate (n = 51) vs placebo (n = 46) (subgroups of larger extension study)	Change in BMD at lumbar spine and other sites Morphometric vertebral fracture incidence Safety Outcomes measured at 2-year follow-up	AS adequately generated AC not clear “Double blinded” Incomplete data not adequately addressed All outcomes not fully reported No other threats to validity	Funded by Procter and Gamble Pharmaceuticals (makers of etidronate, the study drug)

Notes:

a Fracture incidence was considered an exploratory outcome;

b Fracture incidence collected as safety endpoint, no formal analysis planned. No attempt made to exclude trauma-related fractures.

Abbreviations: AC, allocation concealment; AS, allocation sequence; BMD, bone mineral density; WHO, World Health Organization.

Figure 2 Forest plots showing pooled estimates for fracture risk and mortality in patients who continue bisphosphonates after 5 years of therapy versus those who discontinue after 5 years.

Notes: ^aClinical nonvertebral fractures; ^bClinical vertebral fractures; ^cMorphometric vertebral fractures; ^dMortality.

Table 2 Mean percentage change (standard error) in bone mineral density over 5 years in continuation versus discontinuation of bisphosphonate groups

Trial	Continuation/discontinuation	Lumbar spine	Femoral neck	Trochanter
Alendronate
Black et al^Citation17 (FLEX)	Continuation	5.26 (0.24)	0.46 (0.24)	−0.08 (0.22)
	Discontinuation	1.52 (0.29)	−1.48 (0.30)	−3.25 (0.27)
Alendronate
Bone et al^19,^a	Continuation
	5 mg group	2.5 (0.56)	1.0 (0.87)	0.0 (0.87)
	10 mg group	3.7 (0.56)	0.9 (0.87)	1.0 (0.82)
	Discontinuation	0.3 (0.61)	−2.2 (0.87)	−1.0 (0.82)
Etidronate
Miller et al^18,^b	Continuation	1.8 (0.71)	0.5 (0.82)	0.4 (0.76)
	Discontinuation	1.4 (1.11)	–0.9 (0.96)	–0.6 (0.91)

Notes:

a No combined continuation group data available. Standard error calculated from confidence intervals provided in paper;

b Results are from 2-year follow-up.

OVID MedLine search strategy (1950 to January week 4 2010)

No.	Searches	Results
1	Osteoporosis/	27,944
2	Osteoporosis, Postmenopausal/	8648
3	Osteoporosis.mp.	45,270
4	1 or 2 or 3	45,270
5	Bisphosphonate$.mp.	6888
6	Diphosphonates/or alendronate/or clodronic acid/or etidronic acid/	12,926
7	Alendronate.mp.	2624
8	Risedronate.mp.	838
9	Pamidronate.mp.	2175
10	Zoledronic acid.mp.	1348
11	Etidronate.mp.	1048
12	Ibandronate.mp.	487
13	Diphosphonate$.mp.	11,655
14	5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13	16,843
15	4 and 14	5044
16	Time factors/	830,953
17	Follow-up studies/	393,252
18	Follow up studie$.mp.	397,885
19	(stop$ or hold$ or finish$ or withold$ or withdraw$ or withdrew$ or drug holiday$ or skip$ or halt$ or cessat$ or discontinue$ or held or cease$ or suspend$).mp. [mp = title, original title, abstract, name of substance word, subject heading word, unique identifier]	391,767
20	16 or 17 or 18 or 19	1,512,880
21	15 and 20	836
22	Limit 21 to (clinical trial, all or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative	361
	study or controlled clinical trial or randomized controlled trial)
23	Limit 22 to humans	353

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