SERMs and SERMs with estrogen for postmenopausal osteoporosis

Abstract

Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women's Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.

Modulation of bone turnover in orchidectomized rats treated with raloxifene and risedronate

“…The SERM ‘ RAL ’ had been proved to prevent postmenopausal osteoporosis . It did not bind to androgen receptors and had no effects on male reproduction.…”

“…Raloxifene ( RAL ) is a selective oestrogen receptor modulator (SERM), which exhibits agonistic or antagonistic characters in a cell and tissue. RAL mimics the effects of oestrogens in bone without stimulatory effects in most other tissues . The observations that oestrogens may play a role in bone metabolism of men and that SERMs prevent bone loss in ORX male rats raised the possibility that they may be used in the treatment of elderly men without feminizing side effects .…”

Bone Physiology: Bone Cells, Modeling, and Remodeling

“…Estrogen agonists/antagonists, formerly termed selective estrogen receptor modulators (SERMs), which do not stimulate the breast or uterus, can still inhibit bone resorption and prevent bone loss after ovariectomy [ 87 ]. Bone turnover can be decreased by low doses of estrogen, and fracture risk is increased in women with extremely low serum estradiol concentrations [ 88 , 89 ].…”

Circadian transcription factor Dbp promotes rat calvarial osteoprogenitors osteogenic differentiation through Kiss1/GnRH/E2 signaling pathway loop

“…21 Furthermore, several clinical and animal model studies have demonstrated that estrogens function in bone tissue [22][23][24] and have suggested that ER modulators aid in osteoporosis prevention and/or clinical treatment. 25,26 ERs are highly expressed in OPCs, while present at lower levels in osteoclasts. 27 In OPCs, when E2 interacted with the ERα, osteogenic activity is enhanced.…”

“…Estrogens are vital for maintaining bone mineral density in both mice and humans, 21 while E2 is pro‐osteoblastic, and promotes bone formation 21 . Furthermore, several clinical and animal model studies have demonstrated that estrogens function in bone tissue 22‐24 and have suggested that ER modulators aid in osteoporosis prevention and/or clinical treatment 25,26 . ERs are highly expressed in OPCs, while present at lower levels in osteoclasts 27 .…”