Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs. Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERalpha. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERalpha pathways are involved in androgen action on radial bone growth. ERbeta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERalpha.

https://www.hormonebalance.org/images/documents/Androgens%20and%20Bone%20Clin%20Endo%2004%20Vander.pdf

Androgens and bone

Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment.

Many therapeutic regimens in cancer treatment carry the risk of causing or favoring the development of osteoporosis. Therapies in which hypogonadism may occur are most relevant in this respect. Prompt hormone replacement therapy is indicated in these patients. In patients in whom this is undesirable because of a hormone-dependent tumor, the risk of osteoporosis should be assessed by means of osteodensitometry, and prophylactic or therapeutic measures should be instituted if necessary. Early intervention improves outcome because osteoporosis therapy is most effective in preventing deterioration of bone mass. There remains much uncertainty in assessing the risk of combination chemotherapy with regard to the development of osteoporosis. Negative effects on the skeleton have, however, been demonstrated for individual drugs, such as methotrexate and ifosfamide. Negative effects of the tumor itself on bone metabolism may aggravate the degree of osteoporosis. Detailed data and long-term experience to assess the risk are urgently needed in this area and constitute an important research topic for the coming years and decades. This review discusses the most prevalent mechanisms of osteoporosis caused by cancer treatment and outlines therapeutic strategies for the prevention and treatment of therapy-induced bone loss.

Osteoporosis Due to Cancer Treatment: Pathogenesis and Management

The sex hormone estrogen is important for many physiologic processes. Prolonged stimulation of breast ductal epithelium by estrogen, however, can contribute to the development and progression of breast cancer, and treatments designed to block estrogen's effects are important options in the clinic. Tamoxifen and other similar drugs are effective in breast cancer prevention and treatment by inhibiting the proliferative effects of estrogen that are mediated through the estrogen receptor (ER). However, these drugs also have many estrogenic effects depending on the tissue and gene, and they are more appropriately called selective estrogen receptor modulators (SERMs). SERMs bind ER, alter receptor conformation, and facilitate binding of coregulatory proteins that activate or repress transcriptional activation of estrogen target genes. Theoretically, SERMs could be synthesized that would exhibit nearly complete agonist activity on the one hand or pure antiestrogenic activity on the other. Depending on their functional activities, SERMs could then be developed for a variety of clinical uses, including prevention and treatment of osteoporosis, treatment and prevention of estrogen-regulated malignancies, and even for hormone replacement therapy. Tamoxifen is effective in patients with ER-positive metastatic breast cancer and in the adjuvant setting. The promising role for tamoxifen in ductal carcinoma-in-situ or for breast cancer prevention is evolving, and its use can be considered in certain patient groups. Other SERMs are in development, with the goal of reducing toxicity and/or improving efficacy, and future agents have the potential of providing a new paradigm for maintaining the health of women.

Selective Estrogen Receptor Modulators: Structure, Function, and Clinical Use

Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs.

/pdf/selective-estrogen-receptor-modulators-tissue-specificity-3a7ekwujkn.pdf

Selective estrogen receptor modulators: tissue specificity and clinical utility.

Idoxifene, a novel selective estrogen receptor modulator, was tested for its effects on bone loss, serum cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat Idoxifene (05 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD) In an intervention study, idoxifene (05 and 25 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group Idoxifene reduced total serum cholesterol, which was maximal at 05 mg/kg x day Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of estrogen in intact rats Histologically, myometrial and endometrial atrophy were observed in both idoxifene and vehicle-treated Ovx rats In this report, we also provide molecular-based evidence to support the observations in vivo of a novel selective estrogen receptor modulator (SERM) mechanism of action in bone and endometrial cells Idoxifene is an agonist through the estrogen response element (ERE) and exhibits similar postreceptor effects to estrogen in bone-forming osteoblasts Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis However, idoxifene differs from estrogen in a tissue-specific manner In human endometrial cells, where estrogen is a potent agonist through the ERE, idoxifene has negligible agonist activity Moreover, idoxifene was able to block estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study In the uterus, idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium

/pdf/idoxifene-a-novel-selective-estrogen-receptor-modulator-1vjmy3zzrs.pdf

Idoxifene: A Novel Selective Estrogen Receptor Modulator Prevents Bone Loss and Lowers Cholesterol Levels in Ovariectomized Rats and Decreases Uterine Weight in Intact Rats

Objective. To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA).



Methods. AIA was induced in Lewis rats on day 0, and the animals were treated either prophylactically (days 0–16 or days 0–23) or therapeutically (days 10–23) with SK&F 106615. Efficacy was determined by measurements of paw inflammation, bone mineral density (BMD) using dual x-ray absorptiometry, and magnetic resonance imaging (MRI). Joint integrity was also determined histologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound.



Results. Prophylactic treatment (days 0–16) of AIA rats with SK&F 106615 significantly inhibited paw volume at doses of 5–45 mg/kg/day given orally on 5 days each week. Extensive evaluation of joint integrity in rats treated with SK&F 106615 20 mg/kg/day orally for 23 days showed inhibition of paw volume, normalization of BMD, and significant improvement in disease by MRI and histologic assessment compared with the AIA controls. Elevated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10–23) resulted in similar protective effects measured by paw inflammation, BMD, and MRI. In the therapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema.



Conclusion. Symptoms of AIA in rats are significantly reduced by prophylactic and therapeutic treatment with SK&F 106615. Of particular note, this compound appears to exert a protective effect on joint integrity and to have disease-modifying properties.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780390319

Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease including magnetic resonance imaging and bone mineral density measurements

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Idoxifene: A Novel Selective Estrogen Receptor Modulator Prevents Bone Loss and Lowers Cholesterol Levels in Ovariectomized Rats and Decreases Uterine Weight in Intact Rats

Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease including magnetic resonance imaging and bone mineral density measurements