. 2016 Feb 19;31(8):947–957. doi: 10.1007/s11606-016-3603-8

Table 1.

Descriptions of the Included Studies and Bone Outcomes

Author, year ^ref.	Study design and duration	Study Participants	LMWH: Type Daily dose Sample (n)	Control: Type Daily dose Sample (n)	Purpose and duration of treatment	Bone outcomes	Changes in BMD	Number of fractures LMWH/control
Clinical trials
Monreal 1994⁵⁴	Single center Single blinded RCT 6 months	N = 80 (prior VTE, contraindicated to OA) Mean age: 68 years 50 % female	Dalteparin: 10,000 IU n = 40	UFH: 20,000 IU n = 40	Prophylaxis 3–6 months	BMD fractures (vertebral)	Not reported	1/40	6/40
Berrnis 1997⁴⁶	Clinical trial^* 24 months	N = 23 (hemodialysis patients, prior VTE)	24 months LMWH^‡ n = 13	UFH n = 10	Not reported	BMD	FN BMD, (g/cm²): LMWH: 0.003 ± 0.2, P > 0.05 UFH: −0.013 ± 0.02, P < 0.05	NA	NA
FRISC II 1999⁴⁷	Multicenter (59 sites) Factorial Open label RCT 3–6 months	N = 2105 (coronary artery disease, prior VTE) Mean age: 67 years 30 % female	Dalteparin: 10,000–15,000 IU n = 1049	Placebo n = 1056	Prophylaxis 3 months	Fractures (all clinical)	NA	No increase in the risk of fractures
Veiga 2000⁵⁶	Single center Single blinded RCT 12 months	N = 100 (prior VTE, cardiovascular disease or cancer) Mean age: 80 years 60 % female	Enoxaparin: 40 mg n = 50	Acenocoumarol n = 50	Prophylaxis 3–6 months	Fractures (all clinical)	NA	2/50	0/50
Lai 2001⁵³	Single center Cross-over trial 20 months	N = 40 (hemodialysis patients, prior VTE) Mean age: 42 years 40 % female	Nadroparin: 10,000-15,000 IU n = 40	UFH: 5000–7500 IU n = 40	Prophylaxis LMWH: 8 months UFH: 12 months	BMD Bone Turnover Markers	NS changes in BMD at FN, trochanter and LS; changes at Ward’s (P > 0.05): LMWH: + 0.75 % UFH: −2.4 %	NA	NA
Grassman 2001⁴⁸	Multicenter (4 sites) Double blinded RCT 6 months	N = 118 (coronary artery disease, prior VTE) Mean age: 67 years 30 % female	Certoparin: 80 mg n = 59	Placebo n = 59	Prophylaxis 3 months	BMD	NS changes in BMD	NA	NA
Hull 2007⁵¹ ^†	Multicenter (22 sites) Open label RCT (Main LITE Broad) 12 months	N = 737 (prior VTE, cardiovascular disease or cancer) Mean age: 54 % >60 years 46 % female	Tinzaparin: 175 IU/kg n = 369	Usual care: short-term UFH and warfarin n = 368	Therapy 3–6 months	Fractures (all clinical)	NA	4/369	7/368
Hull 2006⁵⁰ ^†	Multicenter (22 sites) Open label RCT (Main LITE Cancer) 12 months	N = 200 (prior VTE and cancer, solid tumors and hematologic) Mean age: 69 % >60 years 49 % female	Tinzaparin: 175 IU/kg n = 100	Usual care: short-term UFH and warfarin n = 100	Therapy 3–6 months	Fractures (all clinical)	NA	3/100	5/100
Hull 2009⁵²	Multicenter Open label RCT (Home LITE) 22 centers 12 months	N = 480 (first or recurrent VTE) Mean age: 50 % >60 years 42 % female	Tinzaparin: 175 IU/kg n = 240	Usual care: short-term tinzaparin and warfarin n = 240	Therapy 3 months	Fractures (all clinical)	NA	2/240	5/240
Haas 2012⁴⁹	Multicenter (39 sites) Two double-blinded RCTs (TOPIC-1; TOPIC-2) 6 months	N1 = 352 (disseminated breast cancer-RCT 1) N2 = 546 (non-small-cell lung carcinoma-RCT 2) Mean age: 55 (RCT 1); 60 (RCT 2) % female: 17 (RCT 2)	Certoparin: 3000 IU (RCT 1) n = 174 (RCT 2) n = 273	Placebo (RCT 1) n = 178 (RCT 2) n = 273	Prophylaxis 3 months	Fractures (osteoporotic)	NA	0/174 1/268	0/177 0/264
Serra 2013⁵⁵	Single center Open label RCT 60 months	N = 284 (chronic venous ulcers) Mean age: 69 years 78 % female	Nadroparin: 2850 IU/day n = 142	Compression therapy n = 142	Therapy 12 months	BMD	No osteoporosis in the LMWH group	NA	NA
Observational cohort studies
Monreal 1991⁵⁸	Prospective cohort 3 months	N = 80 (prior VTE contraindicated OA) Mean age: 67 years 55 % female	Dalteparin: 5,000 IU n = 24	UFH: 10,000 IU n = 28 Coumarin n = 28	Prophylaxis 3 months	BMD and fractures (vertebral)	% Change in LS BMD: −2.4 % (Dalteparin); −3.0 % (UFH); −2.0 % (Coumarin) % change in FN BMD: −2.8 % (Dalteparin); −4.9 % (UFH); −2.1 % (Coumarin)	1/24	3/28 (UFH) 1/28
Rostoker 1995⁵⁹	Prospective cohort 48 months	N = 55 (nephrotic syndrome) Mean age: 48 years 50 % female	Long-term Enoxaparin: 40 mg n = 30	Short-term Enoxaparin 40 mg n = 25	Prophylaxis long term: 6–48 months Short term: <4 months	BMD	BMD remained unchanged in one postmenopausal patient	NA	NA
Warwrzynska 2001⁶⁰	Prospective cohort 12 months	N = 54 (prior VTE) Mean age: 57 years 50 % female	Nadroparin: 15,000 IU n = 15 Enoxaparin: 1 mg/kg n = 15	Acenocoumarol n = 24	Prophylaxis 3–6 months	BMD	% change in LS BMD: Nadroparin: −1.2 % (3 m); Enoxaparin: −3.6 % (6–12 m); Coumarin: −1.2 % (3 m); −1.7 % (6–12 m) % change in FN BMD: Nadroparin: −1.2 % (3 m); Enoxaparin: −3.6 % (6–12 m); Coumarin: −1.2 % (3 m); −1.7 % (6–12 m)	NA	NA
Warwrzynska 2003⁶¹ ^†	Prospective cohort 24 months	N = 86 (prior VTE) Mean age: 48 years 50 % female	Nadroparin: 15,000 IU n = 15 Enoxaparin: 1 mg/kg n = 42	Acenocoumarol n = 29	Prophylaxis 6–24 months	BMD	% change in LS BMD: Nadroparin: −1.2 %(3 m); Enoxaparin: −4.0 %(12 m); −3.8 %(24 m) Coumarin: −1.7 % (12 m); −2.3 %(24 m) % change in FN BMD: Nadroparin: −1.3 %(3 m); Enoxaparin: −3.1 %(12 m); −4.8 % (24 m) Coumarin: −1.8 % (12 m); −2.5 % (24 m)	NA	NA
Grzegorzewska 2008⁵⁷	Retrospective cohort 24 months	N = 30 (uremic dialysis) Mean age: 65 years (LMWH) and 48 years (no-LMWH) % female: not reported	Nadroparin or enoxaparin n = 14	None n = 16	Prophylaxis 24 months	BMD	LS BMD T-score < −2.5: 4/14 vs. 0/16 FN BMD T-score < −2.5: 6/14 vs. 1/16, differences remained significant (P < 0.05) in a multivariable analysis adjusting for age, sex, coffee consumption and drugs	NA	NA

LMWH = low-molecular-weight heparin; N = total study sample; BMD = bone mineral density; LS = lumbar spine; FN = femoral neck; RCT = randomized controlled trials; UFH = unfractionated heparin; VTE = venous thromboembolism; OA = oral anticoagulants; IU = International Factor Xa Inhibitory Units; NS = not significant (P > 0.05); NA = not applicable; m = months; ^*reported as abstract; ^†same study⁵⁰ or the extension of the same study⁶¹