The use of selective estrogen receptor modulators on bone health in men

Figures & data

Table 1. The effects of SERMs on bone health in animal studies.

Researcher (year)	Animal model	Treatment and dose	Duration	Mode	BMD	Micro-structure	Bone markers	Bio-mechanical
Jardi et al. (2017) [42]	Male C57BL/6J mice	Tamoxifen (190 mg/kg) – 2 doses	2 days	po	–	↔	Oc: ↔	↔
		Tamoxifen (190 mg/kg) – 4 doses	4 days		–	↑	Oc: ↔	↔
		Tamoxifen (190 mg/kg) – 10 doses	10 days		–	↑	Oc: ↑	↓
Kaczmarczyk-Sedlak et al. (2006) [44]	Mature male Wistar rats	Raloxifene (5 mg/kg, daily)	4 weeks	po	–	↔	–	–
		Raloxifene (5 mg/kg, daily) + tacrolimus (0.3 mg/kg)			–	↑	–	–
		Raloxifene (5 mg/kg, daily) + tacrolimus (0.6 mg/kg)			–	↑	–	–
Ke et al. (2000) [37]	ORX male Sprague-Dawley rats (10-month-old)	Lasofoxifene (1 µg/kg, daily)	60 days	po	↔	↔	–	↔
		Lasofoxifene (10 µg/kg, daily)			↑	↑	–	↑
		Lasofoxifene (100 µg/kg, daily)			↑	↑	–	↑
Ke et al. (2001) [46]	Male Sprague-Dawley rats (15-month-old)	Lasofoxifene (0.01 mg/kg, daily)	6 months	po	–	↑	Oc: ↓	↑
		Lasofoxifene (0.1 mg/kg, daily)			–	↑	Oc: ↓	↑
Khedr et al. (2013) [32]	ORX male Wistar rats (12-week-old)	Raloxifene (3 mg/kg, 3 times/week)	6 weeks	po	↑	↑	Oc: ↔	–
		Raloxifene (3 mg/kg, 3 times/week) + risedronate (5 µg/kg, 2 times/week)			↑	↑	Oc: ↓	–
Meixner et al. (2017) [45]	C57BL/6J male mice (16-week-old)	Raloxifene (0.5 mg/kg, 5 times/week) + zoledronate	4 weeks	s.c	–	↑	–	↑
		Raloxifene (2.0 mg/kg, 5 times/week) + zoledronate			–	↑	–	↑
Nowinska et al. (2007) [47]	Methotrexate- treated male Wistar rats	Raloxifene hydrochloride (5 mg/kg, daily)	28 days	po	–	–	–	↔
Onoe et al. (2000) [30]	ORX male	Raloxifene (100 µg/kg, daily)	2 weeks	s.c	↑	↑	–	–
Sato et al. (2017) [38]	ORX C57BL/6 male mice	Raloxifene (3 mg/kg, 5 times/week)	5 weeks	Intragastric infusion	↔	↑	–	–
		Bazedoxifen (3 mg/kg, 5 times/week)			↔	↑	–	–
		Tamoxifen (1 mg/kg, 5 times/week)			↔	↑	–	–
Borjesson et al. (2013) [39]	ORX male ERα-deficient mice (20-weeks-old)	Raloxifene (120 μg/mouse/day)	3 weeks	s.c	↑	↔	–	↔
		Lasofoxifene (8 μg/mouse/day)			↑	↑	–	↔
		Bazedoxifene (48 μg/mouse/day)			↑	↔	–	↑
Broulik (2000) [27]	Adult ORX male strain H (Velaz Prague) rats (n = 32)	Tamoxifen (0.1 mg/day)-mix in diet	3 months	po	↑	↑	–	–
Broulik and Broulikova (2007) [29]	Adult ORX male strain H (Velaz Prague) rats (n = 32)	Raloxifene (5.0 mg/kg/day)- mix in diet	3 months	po	↑	↑	–	–
Filipovic et al. (2015) [41]	ORX male Wistar rats (15-month-old) (n = 24)	Tamoxifen (0.3 mg/kg, daily)	3 weeks	s.c	–	↑	Oc: ↓	–
Fitts et al. (2001) [26]	ORX male Sprague Dawley rats (78-80 day old) (n = 48)	Estradiol (E2) benzoate (50 µg/kg) 3 times weekly	6 weeks	s.c	↑	–	–	–
		Testosterone (T3) (10 µg/kg) once daily		i.p	↔	–	–	–
		Tamoxifen (0.5 mg/kg) once daily		s.c	↔	–	–	–
		T3 + tamoxifen			↑	–	–	–
		T3+ E2 benzoate			↑	–	–	–
Fitts et al. (2004) [25]	ORX male Sprague Dawley rats (79–84 days old) (n = 44)	Testosterone 17b-propionate (TP) (1 mg/kg and 10 mg/kg)daily	6 weeks	s.c	↔	–	–	–
		Tamoxifen (1 mg/kg) daily			↔	–	–	–
		TP + tamoxifen			↑	–	–	–
Folwarczna et al. (2009) [36]	Mature male Wistar rats (n = 28)	Raloxifene hydrochloride (5 mg/kg) daily	4 weeks	po	↑	–	–	↔
		Tacrolimus + raloxifene hydrochloride			↑	–	–	↔
Folwarczna et al. (2007) [31]	Adult male Wistar rats (n = 14)	Raloxifene hydrochloride (5 mg/kg)	4 weeks	po	↑	↔	–	↔
Starnes et al. (2007) [40]	C57BL/6J mice	4-hydroxytamoxifen (0.1 mg, bi-weekly begin at 5 weeks)	12 weeks	i.p	–	↑	–	–
Stuermer et al. (2009) [34]	ORX Sprague-Dawley rats (3 months old)	Raloxifene (3.35 mg at average/day)	12 weeks	po	↑	↑	–	↑
Sturmer et al. (2006) [33]	ORX Sprague-Dawley rats (3 months old)	Raloxifene (3.35 mg at average/day)	12 weeks	po	↑	–	–	↑
Zhong et al. (2015) [43]	Wild-type male mice	Tamoxifen (1 mg/kg/day) – 4 consecutive days	1 month	i.p	–	↔	OC: ↔	↔
		Tamoxifen (10 mg/kg/day) – 4 consecutive days			–	↔	OC: ↔ CTX: ↔	↑
		Tamoxifen (100 mg/kg/day) – 4 consecutive days			–	↑	OC: ↔ CTX: ↓	↑
		Tamoxifen (100 mg/kg/day) –once			–	↑	–	–
		Tamoxifen (300 mg/kg/day) –once			–	↑	–	–
Karimian et al. (2008) [28]	Male Sprague Dawley rats (4-week-old)	Tamoxifen (40 mg/kg, daily)	4 weeks	po	↓	↓	–	↓

Table 2. The effects of SERMs on bone health in human studies.

Researcher (year)	Study type	Characteristics of the subjects	Interventions (Drug and dose)	Study period	Findings
Smith et al. (2004) [24]	Randomized controlled trial	Men with nonmetastatic prostate cancer receiving a GnRH agonist for 6 months or more (n = 48)	Raloxifene (60 mg/day	12 months	Men receiving raloxifene had higher total hip and trochanter BMD and lower bone markers (amino-terminal propeptide of type I collagen by and urinary excretion of deoxypyridinoline)
Smith et al. (2008) [48]	Randomized, double-blind, placebo controlled, phase III trial	Men with prostate cancer and serum PSA ≤4 ng/ml (n = 197; age: ≥50 years)	Toremifene (80 mg/day)	12 months	Toremifene increased BMD at lumbar spine, total hip and femoral neck.
Smith et al. (2010) [49]	Randomized, double-blind, placebo controlled phase III trial	Men receiving ADT for prostate cancer and at increased risk for fracture or osteopenia at the femoral neck or L1–L4 lumbar spine (n = 1284; age: ≥50 years)	Toremifene (80 mg/day)	2 years	Toremifene reduced relative risk of new vertebral fractures, increased BMD at lumbar spine, total hip, and femoral neck Toremifene decreased bone turnover markers (ALP, C-telopeptide and OC)
Smith et al. (2011) [50]	Randomized, double-blind, placebo controlled, phase III trial	Men with prostate cancer and serum PSA ≤4 ng/ml (n = 647; age: ≥50 years)	Toremifene (80 mg/day)	24 months	Toremifene decreased relative risk of new vertebral fracture and incidence of non-traumatic fracture Toremifene increased BMD at lumbar spine, total hip and femoral neck. Toremifene decreased bone-specific markers (ALP, C-telopeptide and OC)
Doran et al. (2001) [51]	Randomized blinded study	Elderly men (n = 50; age: ≥60 years)	Rolaxifene (60 mg/day)	6 months	Level of bone-specific ALP did not differ between the raloxifene-treated and placebo groups.
Duschek et al. (2004) [52]	Double-blind, placebo-controlled study	Healthy men (n = 30; age: 60–70 years)	Raloxifene (120 mg/day)	3 months	Raloxifene increased LH, FSH and sex steroid hormones No effects on bone resorption marker.
Uebelhart et al. (2004) [53]	Randomized placebo-controlled, double-blind, two-sequence crossover study	Healthy eugonadal men (n = 43; age: 49–70 years)	Raloxifene (120 mg/day)	6 weeks raloxifene (8 weeks washout period)	Raloxifene increased total testosterone, bioavailable testosterone, total estradiol, and bioavailable estradiol levels Raloxifene decreased serum OC and ALP.
Yu et al. (2015) [54]	Prospective randomized 1:1:1 phase 2 open-label multicenter trial	Men with advanced prostate cancer (n = 159; age: 45–80 years)	GTx-758 1000 mg (two 500 mg tablets) or 2000 mg	300 days	GTx-758 decreased free testosterone, CTX, and bone-specific ALP.
Lin et al. (2014) [77]	Cohort study	Osteoporosis patients with newly diagnosed vertebral or hip fracture (n= 68,808; age: >50-year old)	Raloxifene	Between 2003 and 2007	There was no excess risk for osteonecrosis of the jaw in osteoporosis patients aged >50 years old using raloxifene.
Vestergaard et al. (2011) [55]	Nationwide cohort study (Denmark)	Patients exposed to drugs against osteoporosis	Raloxifene	Between1996 and 2006	Increased risk of subtrochanteric fractures was present before the start of raloxifene but not after the initiation of the therapy.

Jardi F, Laurent MR, Dubois V, et al. A shortened tamoxifen induction scheme to induce CreER recombinase without side effects on the male mouse skeleton. Mol Cell Endocrinol. 2017;452:57–63.

 PubMed Web of Science ®Google Scholar

Kaczmarczyk-Sedlak I, Folwarczna J, Cegiela U, et al. Raloxifene does not affect the changes in bone histomorphometric parameters induced by low dose tacrolimus in male rats. Acta Pol Pharm. 2006;63:301–306.

 PubMed Web of Science ®Google Scholar

Ke HZ, Qi H, Crawford DT, et al. Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. Endocrinology. 2000;141:1338–1344.

 PubMed Web of Science ®Google Scholar

Ke HZ, Qi H, Chidsey-Frink KL, et al. Lasofoxifene (CP-336,156) protects against the age-related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats. J Bone Miner Res. 2001;16:765–773.

 PubMed Web of Science ®Google Scholar

Khedr NF, El-Ashmawy NE, El-Bahrawy HA, et al. Modulation of bone turnover in orchidectomized rats treated with raloxifene and risedronate. Fundam Clin Pharmacol. 2013;27:526–534.

 PubMed Web of Science ®Google Scholar

Meixner CN, Aref MW, Gupta A, et al. Raloxifene improves bone mechanical properties in mice previously treated with zoledronate. Calcif Tissue Int. 2017;101:75–81.

 PubMed Web of Science ®Google Scholar

Nowinska B, Cegiela U, Folwarczna J, et al. Effects of raloxifene on development of the methotrexate-induced changes in bone mechanical properties of male rats. Pharmacol Rep. 2007;59:359–364.

 PubMed Web of Science ®Google Scholar

Onoe Y, Miyaura C, Ito M, et al. Comparative effects of estrogen and raloxifene on B lymphopoiesis and bone loss induced by sex steroid deficiency in mice. J Bone Miner Res. 2000;15:541–549.

 PubMed Web of Science ®Google Scholar

Sato Y, Tando T, Morita M, et al. Selective estrogen receptor modulators and the vitamin D analogue eldecalcitol block bone loss in male osteoporosis. Biochem Biophys Res Commun. 2017;482:1430–1436.

 PubMed Web of Science ®Google Scholar

Borjesson AE, Farman HH, Engdahl C, et al. The role of activation functions 1 and 2 of estrogen receptor-alpha for the effects of estradiol and selective estrogen receptor modulators in male mice. J Bone Miner Res. 2013;28:1117–1126.

 PubMed Web of Science ®Google Scholar

Broulik PD. Tamoxifen prevents bone loss in castrated male mice. Horm Metab Res. 2000;32:181–184.

 PubMed Web of Science ®Google Scholar

Broulik PD, Broulikova K. Raloxifen prevents bone loss in castrated male mice. Physiol Res. 2007;56:443–447.

 PubMed Web of Science ®Google Scholar

Filipovic B, Sosic-Jurjevic B, Ajdzanovic V, et al. Tamoxifen stimulates calcitonin-producing thyroid C-cells and prevents trabecular bone loss in a rat model of androgen deficiency. J Anat. 2015;226:489–496.

 PubMed Web of Science ®Google Scholar

Fitts JM, Klein RM, Powers CA. Estrogen and tamoxifen interplay with T(3) in male rats: pharmacologically distinct classes of estrogen responses affecting growth, bone, and lipid metabolism, and their relation to serum GH and IGF-I. Endocrinology. 2001;142:4223–4235.

 PubMed Web of Science ®Google Scholar

Fitts JM, Klein RM, Powers CA. Comparison of tamoxifen and testosterone propionate in male rats: differential prevention of orchidectomy effects on sex organs, bone mass, growth, and the growth hormone-IGF-I axis. J Androl. 2004;25:523–534.

 PubMedGoogle Scholar

Folwarczna J, Kaczmarczyk-Sedlak I, Pytlik M, et al. Effect of low-dose tacrolimus coadministered with raloxifene on the skeletal system in male rats. Acta Pol Pharm. 2009;66:207–212.

 PubMed Web of Science ®Google Scholar

Folwarczna J, Sliwinski L, Cegiela U, et al. Raloxifene similarly affects the skeletal system of male and ovariectomized female rats. Pharmacol Rep. 2007;59:349–358.

 PubMed Web of Science ®Google Scholar

Starnes LM, Downey CM, Boyd SK, et al. Increased bone mass in male and female mice following tamoxifen administration. Genesis. 2007;45:229–235.

 PubMed Web of Science ®Google Scholar

Stuermer EK, Sehmisch S, Tezval M, et al. Effect of testosterone, raloxifene and estrogen replacement on the microstructure and biomechanics of metaphyseal osteoporotic bones in orchiectomized male rats. World J Urol. 2009;27:547–555.

 PubMed Web of Science ®Google Scholar

Sturmer EK, Seidlova-Wuttke D, Sehmisch S, et al. Standardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene. J Bone Miner Res. 2006;21:89–96.

 PubMed Web of Science ®Google Scholar

Zhong ZA, Sun W, Chen H, et al. Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice. Bone. 2015;81:614–619.

 PubMed Web of Science ®Google Scholar

Karimian E, Chagin AS, Gjerde J, et al. Tamoxifen impairs both longitudinal and cortical bone growth in young male rats. J Bone Miner Res. 2008;23:1267–1277.

 PubMed Web of Science ®Google Scholar

Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841–3846.

 PubMed Web of Science ®Google Scholar

Smith MR, Malkowicz SB, Chu F, et al. Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol. 2008;179:152–155.

 PubMed Web of Science ®Google Scholar

Smith MR, Morton RA, Barnette KG, et al. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol. 2010;184:1316–1321.

 PubMed Web of Science ®Google Scholar

Smith MR, Malkowicz SB, Brawer MK, et al. Toremifene decreases vertebral fractures in men younger than 80 years receiving androgen deprivation therapy for prostate cancer. J Urol. 2011;186:2239–2244.

 PubMed Web of Science ®Google Scholar

Doran PM, Riggs BL, Atkinson EJ, et al. Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res. 2001;16:2118–2125.

 PubMed Web of Science ®Google Scholar

Duschek EJ, Gooren LJ, Netelenbos C. Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men. Eur J Endocrinol. 2004;150:539–546.

 PubMed Web of Science ®Google Scholar

Uebelhart B, Herrmann F, Pavo I, et al. Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels. J Bone Miner Res. 2004;19:1518–1524.

 PubMed Web of Science ®Google Scholar

Yu EY, Getzenberg RH, Coss CC, et al. Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer. Eur Urol. 2015;67:334–341.

 PubMed Web of Science ®Google Scholar

Lin TC, Yang CY, Kao Yang YH, et al. Incidence and risk of osteonecrosis of the jaw among the Taiwan osteoporosis population. Osteoporos Int. 2014;25:1503–1511.

 PubMed Web of Science ®Google Scholar

Vestergaard P, Schwartz F, Rejnmark L, et al. Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene. Osteoporos Int. 2011;22:993–1001.

 PubMed Web of Science ®Google Scholar