Osteoporosis in Older Adults
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Keywords:
Teriparatide
Denosumab
Raloxifene
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Teriparatide
Bone remodeling
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Several lines of evidence demonstrate that the objective of osteoporosis treatment consists in the prophylaxis of osteoporotic fractures. With the endpoint of osteoporosis treatment thus clarified, currently, the selective estrogen receptor modulator (SERM) raloxifine represents the mainstay of therapy for osteoporosis, together with the antiresorptive agents bisphosphonates. Thus, this review has drawn mainly on the results of the MORE study to explore the efficacy of raloxifene in inhibiting bone metabolism, increasing bone mineral density effects, and preventing bone fractures. Notably, the available evidence for raloxifene suggests that the efficacy of raloxifene in preventing bone fractures has not only to do with bone mineral density but also to do with bone quality.
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Selective estrogen receptor Modulator (SERM)은 에스트로겐 수용체와 결합하여, 조직마다 다르게 작용하여 길항이나 대항의 역할을 수행한다. 이러한 SERM 중의 하나인 raloxifene은 여성호르몬 수용체와 nanomolar 친화력을 가지고, 조직에 따라 길항제와 대항제로 작용한다. 즉 뼈와 지질에는 에스트로겐 길항제로 작용하고, 유방과 자궁에는 대항제로 작용한다. Tamoxifen은 다른 종류의 SERM으로 길항제와 대항제의 양면성을 자궁 내막에 작용한다. 그러므로 자궁근종은 에스트로겐 의존성이므로 SERM을 이용하여 사람 자궁근종 세포에 투여함으로써 치료의 가능성을 보고자 이 연구를 계획하였다.
자궁근종과 정상 자궁 근 세포를 일차 배양하여 에스트로겐의 투여 전후의 반응을 보았으며, SERM 투여후의 반응을 MTS 및 생존세포수 계산을 하였고, 세포주기회로 및 세포자멸사를 보기 위해 FACS와 Western-blot을 시행하였다.
일차 배양된 자궁근종와 정상 자궁근 세포에서 에스트로겐과 황체호르몬 수용체의 발현을 확인하고 수용체 양성군과 음성군으로 구별하였다. 에스트로겐 수용체 음성군에서는 에스트로겐을 10^-12에서 10^-6 mol/L까지 용량을 증가하면서 투여하였으나 세포의 증식은 자궁근종 세포나 정상에서는 보이지 않았다. 반대로 에스트로겐 수용체양성군에서는 에스트로겐을 용량의 증가와 투여 일수를 증가하여 세포의 증식이 용량에 비례하여 증가하는 것을 보여주었다. 자궁근종와 정상 자궁근 세포에 에스트로겐을 10^-6 mol/L을 6일간 투여 후 raloxifene을 10^-11에서 10^-7 mol/L까지 용량을 증가하면서 투여하여, 에스트로겐 수용체 음성군에서는 세포 증식의 억제가 거의 없었으나, 양성군에서는 증식의 억제를 관찰하였다. 같은 조건으로 tamoxifen을 10^-11에서 10^-7 mol/L까지 용량을 증가하면서 투여하여, 에스트로겐 수용체 음성군에서는 변화가 없었고, 수용체 양성군에서는 증식의 억제가 관찰되었으나 raloxifene의 증식 억제보다는 적었다. ELT-3 세포주에 tsmoxifen, raloxifene을 투여하여 효과를 비교하여, 두 약제에 모두 세포 증시 억제의 효과를 확인하였다. ELT-3 세포를 FACS를 이용한 세포 주기회로 분석에서 어느 특정한 주기도 증가하는 것을 보이지 않았다. ELT-3 세포를 FACS를 이용한 세포 주기회로 분석에서 어느 특정한 주기도 증가하는 것을 보이지 않았다. 세포 증식의 억제가 세포자멸사와 세포 주기 회로에 관계하는 유전자의 발현을 보았으나, 약제 투여 전이나 후의 발현의 차이가 없었다.
이상의 결과로 보아 SERM은 자궁근종의 세포 증식을 억제하는 역할을 하며, raloxifene의 억제작용이 tamoxifen보다 우수하여 raloxifene이 가임기 여성의 자궁근종의 약물 치료법에 가능성을 보여주었다고 생각한다. 향후 좀더 많은 조사 군을 상대로 다양한 용량에 따른 변화를 조사하여, SERM이 자궁근종에 미치는 기전을 더 확실하게 밝혀, raloxifene이 가임기 여성의 자궁근종 약물치료 개발에 길잡이가 될 것으로 사료된다.
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Teriparatide
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Teriparatide
Raloxifene
Postmenopausal osteoporosis
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Abstract Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. These compounds were initially called “antiestrogens,” but it was subsequently recognized that this inadequately described their spectrum of activities. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis. This review will explore the preclinical and clinical pharmacology of raloxifene, and compare it to other SERMs currently available for clinical use.
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Bone remodeling
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Abstract Background Continuous use of glucocorticoids (GCs) has become the primary cause of secondary osteoporosis. Bisphosphonate drugs were given priority over denosumab and teriparatide in the 2017 American College of Rheumatology (ACR) guidelines but have a series of shortcomings. This study aims to explore the efficacy and safety of teriparatide and denosumab compared with those of oral bisphosphonate drugs. Methods We systematically searched studies included in the PubMed, Web of Science, Embase, and Cochrane library databases and included randomized controlled trials that compared denosumab or teriparatide with oral bisphosphonates. Risk estimates were pooled using both fixed and random effects models. Results We included 10 studies involving 2923 patients who received GCs for meta-analysis, including two drug base analyses and four sensitivity analyses. Teriparatide and denosumab were superior to bisphosphonates in increasing the bone mineral density (BMD) of the lumbar vertebrae [teriparatide: mean difference [MD] 3.98%, 95% confidence interval [CI] 3.61–4.175%, P = 0.00001; denosumab: MD 2.07%, 95% CI 0.97–3.17%, P = 0.0002]. Teriparatide was superior to bisphosphonates in preventing vertebral fractures and increasing hip BMD [MD 2.39%, 95% CI 1.47–3.32, P < 0.00001]. There was no statistically significant difference between serious adverse events, adverse events, and nonvertebral fracture prevention drugs. Conclusions Teriparatide and denosumab exhibited similar or even superior characteristics to bisphosphonates in our study, and we believe that they have the potential to become first-line GC-induced osteoporosis treatments, especially for patients who have previously received other anti-osteoporotic drugs with poor efficacy.
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Objectives In our previous 24-month study, we observed that teriparatide had some advantages over denosumab for bone mineral density (BMD) in glucocorticoid-induced osteoporosis (GIO) patients with prior bisphosphonate treatment. We conducted this extension study to investigate whether the advantage of teriparatide obtained in the first 2 years would be maintained after the switch to denosumab. Materials and Methods We switched patients who had completed 24-month daily teriparatide treatment to denosumab (switch group, n=18) and compared their BMD every 6 months up to 48 months with the group who continued to receive denosumab (denosumab group, n=16). Results At 48 months, the lumbar spine BMD was significantly increased from baseline in both groups (denosumab: 10.4 ± 8.7%, p<0.001; switch: 14.2 ± 6.8%, p<0.001). However, a significant increase in femoral neck BMD from baseline occurred only in the switch group (11.2 ± 14.6%, p<0.05); denosumab (4.1 ± 10.8%). The total hip BMD increased significantly from baseline in both groups (denosumab: 4.60 ± 7.4%, p<0.05; switch: 7.2 ± 6.9%, p<0.01). Femoral neck BMD was significantly increased in the switch versus the denosumab group (p<0.05). Conclusion In GIO patients with prior bisphosphonate treatment, the advantage of teriparatide may be maintained after the treatment period. A continuous increase in BMD can be expected with teriparatide followed by denosumab.
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Osteoporosis is uncommon before menopause and dramatically increases in prevalence thereafter. That is why estrogens provide protection against osteoporosis. Studies of women receiving estrogen replacement have demonstrated improvements in bone mineral density (BMD) as well as endothelial function. Recent randomized trials, however, have produced equivocal results and raised questions about whether combined hormonal replacement therapy (HRT) prevents later cardiovascular events. Investigations of alternatives to HRT have suggested that selective estrogen receptor modulators (SERMs) may confer cardiovascular and osteoporosis protection. Raloxifene is a second-generation SERM used for the prevention and treatment of postmenopausal osteoporosis. Raloxifene decreases the incidence of vertebral fractures by 30-50% in postmenopausal women with osteoporosis. We also studied its effect on postmenopausal elderly women with osteoporosis.
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