Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys

Hotchkiss, Charlotte E.; Stavisky, Ronda C.; Nowak, Jette; Brommage, Robert; Lees, Cynthia J.; Kaplan, Jay R.

doi:10.1016/s8756-3282(01)00465-3

Cited by 26 publications

(17 citation statements)

References 44 publications

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“…Dose equivalents approximated a standard estrogen therapy dose of E 2 for postmenopausal women and low (L 1 ), target (L 2 ), and high (L 3 ) human-equivalent doses of levormeloxifene. Estradiol treatment resulted in trough serum concentrations of~50 to 200 pg/mL (Hotchkiss et al 2001), comparable to those seen in the midfollicular phase of intact animals (Weinbauer et al 2008) and premenopausal women (e.g., Smith et al 2011;Nagata et al 2011). Serum levormeloxifene concentrations measured by high-performance liquid chromatography (Kiehr and Christensen 1999) averaged 10.9, 18.5, and 51.2 ng/mL for L 1 , L 2 , and L 3 doses, respectively (Hotchkiss et al 2001), comparable to those reported in women receiving similar doses (Skrumsager et al 2002).…”

Section: Study Design and Treatmentsmentioning

confidence: 99%

“…Ovariectomies were performed by an experienced veterinary surgeon at Wake Forest School of Medicine according to standard procedures. Treatments were administered once daily 7 d/wk between 9 a.m. and 11 a.m. in a Crystal Light vehicle by voluntary oral dosing from a syringe for 18 mo (Hotchkiss et al 2001). Because the study was also designed to determine treatment effects on atherosclerosis, all animals were fed a diet designed to mimic the amount of fat, cholesterol, and other nutrients consumed in many industrialized nations.…”

Section: Study Design and Treatmentsmentioning

confidence: 99%

“…The diet was custom formulated at Wake Forest School of Medicine to minimize soy phytoestrogens, which are present in standard monkey chow. Additional details on the diet are provided elsewhere (Hotchkiss et al 2001).…”

Section: Study Design and Treatmentsmentioning

confidence: 99%

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Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

et al. 2011

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Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys (Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17b-estradiol (E 2 ), (3) 0.5 mg/kg levormeloxifene (L 1 ), (4) 1.0 mg/kg levormeloxifene (L 2 ), and (5) 5.0 mg/kg levormeloxifene (L 3 ). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo (p < .0001 for all). The target dose of levormeloxifene (L 2 ) resulted in higher serum concentrations of cortisol (þ63%), dehydroepiandrosterone-sulfate (þ73%), and androstenedione (þ37%) compared with the placebo group (p < .05 for all). In contrast, E 2 resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E 2 and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo (p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E 2 , may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.

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Section: Study Design and Treatmentsmentioning

confidence: 99%

Section: Study Design and Treatmentsmentioning

confidence: 99%

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Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

et al. 2011

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“…Among these are raloxifene, lasofoxifene, and levormeloxifene, which inhibited bone turnover and maintained spine BMD in ovariectomized cynomolgus monkeys after 1 to 2 yr of treatment Hotchkiss et al 2001;Lees et al 2002). Tamoxifen acted as a partial agonist in estrogen-depleted cynomolgus bone by reducing bone turnover (alkaline phosphatase) with no effect on overall spine BMD after 30 mo of treatment.…”

Section: Hormonal Therapiesmentioning

confidence: 99%

“…Estrogen was superior in preventing ovariectomy-induced spinal bone loss Hotchkiss et al 2001;Lees et al 2001). Unlike the SERM (levormeloxifene) tested in one study, estrogen also had a beneficial effect at cortical sites .…”

Section: Hormonal Therapiesmentioning

confidence: 99%

Hormonal Therapies and Osteoporosis

Jerome¹

2004

ILAR Journal

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Osteoporosis, now defined as a disease characterized by low bone mass and a microarchitectural deterioration of bone tissue leading to enhanced bone fragility and fracture risk, is a major public health problem. Classic hormonal therapies to prevent and treat osteoporosis associated with menopause have recently been questioned due to the risk/benefit ratio of prolonged treatment. There is a critical need for safe and effective alternative therapeutics for this disease. Nonhuman primates have been used as models to assess bone changes associated with estrogen deficiency because their trabecular and cortical bone remodeling processes, monthly menstrual cycles, and reproductive-hormone patterns are similar to those of humans. The ovariectomized nonhuman primate has become the preferred model in which to study effects on bone remodeling, particularly with regard to bone mass, architecture, and strength, in fulfillment of studies required by international guidelines for the development of antiosteoporotic drugs. The nonhuman primate is amenable to several methodologies that assess bone quantity and quality, including dual energy x-ray absorptiometry (DXA), quantitative computed tomography (QCT), histology, static and dynamic histomorphometry, and biomechanical testing, as well as assays developed for clinical use, which serve as biomarkers of bone metabolic processes. The use of the nonhuman primate model in the assessment of osteoporosis therapeutics, both hormonal (sex steroids and their analogues, parathyroid hormone) and nonhormonal (bisphosphonates), has provided valuable information on the safety and efficacy as well as the mechanisms of bone loss associated with estrogen deficiency that is directly applicable to the human situation.

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Osteoporosis Therapy: Mechanistic Antiresorptives

Dodge

Bryant

2010

Burger's Medicinal Chemistry and Drug Discovery

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Osteoporosis is defined as the thinning of bone resulting from the imbalance between bone resorption and bone formation, the two cellular mechanisms that regulate the remodeling of skeletal tissue. This loss of bone ultimately results in an increased risk of fracture. One therapeutic approach to treating patients with osteoporosis is to inhibit the process of bone resorption. This has been clinically manifested by the development of a number of large and small molecules that include calcitonin, integrin inhibitors, cathepsin K inhibitors, OPG/RANKL inhibitors, bisphosponates, and SERMS. This chapter describes recent advances in the anti‐resorptive field with a focus on clinically validated targets and the molecules that have been developed to regulate these pathways.

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Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys

Cited by 26 publications

References 44 publications

Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

Hormonal Therapies and Osteoporosis

Osteoporosis Therapy: Mechanistic Antiresorptives

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