Antiresorptive drugs (bisphosphonates), atypical fractures and rebound effect: new evidence of similitude.

BACKGROUND: Homeopathy is based on treatment by similitude ('like cures like') administering to sick individuals substances that cause similar symptoms in healthy individuals, employing the secondary and paradoxical action of the organism as therapeutic response. This vital or homeostatic reaction of the organism can be scientifically explained by the rebound effect of drugs, resulting in worsening of symptoms after suspension of treatment. Bisphosphonates (BPs) reduce 'typical' fractures in patients with osteoporosis, but recent studies report 'atypical' fractures of the femur after stopping the BPs, a rebound effect may be the causal mechanism. METHOD: Review of the literature concerning the relationship between atypical femoral fractures and antiresorptive drugs (bisphosphonates), identifying the pathogenesis of this adverse event. RESULTS: Several studies have described multiple cases of 'atypical' low-impact subtrochanteric stress fractures or complete fractures of the femur. These fractures are often bilateral, preceded by pain in the affected thigh, may have a typical X-ray appearance, and may delayed healing. Rebound of osteoclastic activity after suspension of antiresorptive drugs is a plausible mechanism to explain this phenomenon. CONCLUSION: As for other classes of drugs, the rebound effect of antiresorptive drugs supports Hahnemann's similitude principle (primary action of the drugs followed by secondary and opposite action of the organism), and clarifies this 'unresolved' issue. Unfortunately, the rebound effect is little discussed among health professionals, depriving them of important knowledge ensure safe management of drugs.

Anti-resorptive effect of pilose antler blood (Cervus nippon Temminck) in ovariectomized rats.

Anti-bone resorption activity of pilose antler blood (Cervus nippon Temminck) were evaluated in ovariectomized Wistar rats. The rats were randomly divided into sham operated group (SHAM), ovariectomized group (OVX) and pilose antler blood treated group. The ovariectomized rats were treated with pilose antler blood orally in 4000 microl/kg daily doses for 10 weeks. Compared with SHAM group, serum 17 beta-estradiol level decreased significantly and osteocalcin level increased significantly in OVX group, indicating successful model of osteoporosis. The experiments showed that the bone mineral density of the lumbar spine and left femur in OVX group decreased remarkably compared to SHAM group but normalized by treatment with pilose antler blood. Additionally, serum levels of insulin-like growth factor-land testosterone were lower obviously in OVX group than those in SHAM group but preserved by pilose antler blood treatment. However, no obvious changes in serum levels of calcium, phosphorus, total alkaline phosphatase and osteoprotegerin were observed among three groups. These results suggested that administration of pilose antler blood was effective in alleviating osteoporosis in ovariectomized rats.

[Effects of deer tendons collagen on osteoporosis rats induced by retinoic acid].

OBJECTIVE: To study the effects of deer tendons collagen on osteoporosis rats induced by retinoic acid. METHODS: Male Wistar rats were randomly divided into normal control group, model control group, deer tendons collagen high, medium and low-dose groups, osteoporosis rats of retinoic acid-induced were set up. Changes of body weight, bone weight, bone mineral density, bone histomorphometry, plasma phosphorus, calcium, alkaline phosphatase (ALP), bone mechanics were measured before and after treatment of deer tendons collagen. RESULTS: Compared with model control group,after treated by deer tendons collagen, body weight, bone mineral density, bone weight was increased in varying degrees, bone histomorphometry parameters were significantly different, the ALP in plasma was significantly reduced, contents of Ca, P were increased, all indicators of bone mechanics were significantly higher. CONCLUSION: Deer tendons collagen can prevent and treat retinoic acid-induced osteoporosis of rats.

[Curative effect of Xianling Qianggu koufuye on postmenopausal osteoporosis].

OBJECTIVE: To study the curative effects of Xianling Qianggu koufuye (XLQG) on postmenopausal osteoporosis in ovariectomized female rats. METHOD: Sixty female Sprague-dawley rats aged 12-months were used, 50 of them were ovariectomized and randomly divided into 5 groups: ovariectomized (OVX), OVX + Nylestriol, OVX + XLQG (high dose, middle dose, low dose), and the others were sham-operated group. Rats were treated with drugs starting at the 45 day after the operation for 90 days. Double in vivo fluorochrome labeling was administered to all rats. At the end-point of study, the blood was collected to detecte the contents of ALP and StrACP in serum, and the fourth lumar vertebra (LV4) and femur bone sections were cut and stained for bone histomorphometric analyses, biomechanical analyses and BMP analyses. RESULT: XLQGKFY decreased greatly the StrACP content, increased BMP and bone stiffness, and improved the bone biomechanical property. CONCLUSION: Xianling Qianggu koufuye has a curative effect on postmenopausal osteoporosis, which provides for clinical use.

Neuroendocrine influence on thymic haematopoiesis via the reticulo-epithelial cellular network.

The thymus provides an optimal cellular and humoral microenvironment for a cell line committed differentiation of haematopoietic stem cells. The immigration process requires the secretion of at least one peptide, called thymotaxin, by cells of the reticulo-epithelial (RE) network of the thymic stromal cellular microenvironment. The thymic RE cells are functionally specialised based on their intrathymic location and this differentiation is modulated by various interaction signals of differentiating Thymocytes and other nonlymphatic, haematopoietic stem cells. The subcapsular, endocrine, RE cell layer is comprised of cells filled with periodic acid Shiff's-positive granules, which also express A2B5/TE4 cell surface antigens and MHC Class I (HLA A, B, C) molecules. Thymic nurse cells also produce thymosins beta 3 and beta 4 and display a neuroendocrine cell specific immunophenotype (IP): Thy-1+, A2B5+, TT+, TE4+, UJ13/A+, UJ127.11+, UJ167.11+, UJ181.4+ and presence of common leukocyte antigen (CLA+). Cortical RE cells express a surface antigen, gp200-MR6, which plays a significant role of thymocyte differentiation. Medullar RE cells display MHC Class II (HLA-DP, HLA-DQ, HLA-DR) molecule restriction. Thymic RE cells also produce numerous cytokines that are important in various stages of haematopoietic cell activation and differentiation. The co-existence of pituitary hormone and neuropeptide secretion, as well as the production of a number of interleukins and growth factors, and expression of receptors for all, by RE cells is an unique molecular biological phenomenon. Thymic neuroendocrine polypeptides are the source of self antigens presented by the MHC molecules to differentiating haematopoietic stem cells. On the level of individual RE cells, the numerous projections associated with a single cell, which engulf developing lymphocytes, nurturing and guiding them in their maturation, may differ in their hormone production and/or hormone receptor expression profile, thus allowing a single cell to be involved in distinct, separate steps of the T-cell and other haematopoietic cell maturation process. Thymic RE cells represent an important cellular and humoural network within the thymic microenvironment and are involved in the homeopathic regulation mechanisms of the multicellular organism. The intrathymic T-lymphocyte selection is a complex, multistep process, influenced by several functionally specialised RE cells and under immuno-neuroendocrine regulation control reflecting the dynamic changes of the mammalian organism.

[Effect of kanggusong in prevention and treatment of retinoic acid induced osteoporosis in rats].

Retinoic acid 70 mg/kg.d was given by gastrogavage to Wistar rat for 14 days to induce osteoporosis. Kanggusong (KGS), a mixture of extracts from 8 traditional Chinese drugs, was given to 3 test groups of rats simultaneously in various dosage. Results showed that the KGS displayed obvious action in preventing osteoporosis, the trabecular loss of tibiae and bone loss of compact bone were lowered markedly in KGS groups with high (3.0 g/kg.d) or middle (1.0 g/kg.d) dosage in comparing with control model group, the trabecular area percentage and compact bone area percentage were increased significantly (P < 0.05) which approached to the level of normal control group. KGS could also improve the pathological changes in microstructure of bone, increase the thickness of trabecula and cortex (P < 0.05), reduce the trabecular gap and bone marrow cavity (P < 0.05). The mechanism of KGS might be relevant with its action of suppressing the osteoclast activity and activating osteoblast, resulting a positive balance of bone metabolism, increasing the blood concentration of calcium and estrogen as well as its antagonistic action against the injury of sex glands by retinoic acid.

Effect of oviductus ranae and oviductus ranae eggs on bone metabolism and osteoporosis.

OBJECTIVE: To evaluate the roles or effects of oviductus ranae (OR) or oviductus ranae eggs (ORE) in preventing and treating postmenopausal osteoporosis. METHODS: In vivo experiment: Sixty female adult Wistar rats were randomly divided into 5 groups of 12. To provide an osteoporosis model 4 groups of rats were ovariectomized (OVX), with the 5th being sham operated. Medication commenced 7 days after the operation and lasted continuously for 12 weeks. Sham operated and OVX groups were given equivalent volumes of 5% Tween-80. The other three groups intragastrically received conjugated estrogens (CE), OR or ORE of the corresponding doses. At the 12th week, serum estrogen, bone gla protein (BGP), serum calcium, phosphorus, and alkaline phosphatase (ALP) were assayed; bone mineral densities (BMD) were measured and bone scanning was conducted; uteri were weighed, and weight, volume and length of the femoral bones were determined; and cortical thickness of femoral heads and area of bone trabecula were measured by image analyzer. In vitro experiment: Eighty 10-month old SD rats, with equal numbers of males and females, were randomly divided into 8 groups. Osteoblasts were isolated from neonatal rat calvariae, and the cells were exposed to various concentrations of serum from OR and ORE groups to study the impact of these sera on osteoblastic proliferation, ALP activity and mineralization. Osteoclastic numbers were determined using tartrate resistant acid phosphatase (TRAP). RESULTS: In vivo experiment: The body weight of the four OVX groups increased significantly (P<0.01). Uterine weight of the CE group was the highest (P<0.01); Compared with the model group, estrogen level, BMD, bone scanning/bone imaging index weight of the femoral bones, cortical thickness of femoral heads in the OR and ORE groups increased significantly (P<0.05, P<0.01); femoral volume in the ORE group increased significantly (P<0.05); and the content of osteocalcin, phosphorus, and ALP in serum decreased significantly (P<0.05, P<0.01). In vitro experiment: Sera from OR and ORE groups had notable effects on the proliferation of osteoblasts (P<0.05 and P<0.01, repsectively) and stimulated the formation of calcium nodes (P<0.05, P<0.01), while the enhancement of ALP activity in osteoblasts was significant (P<0.05, P<0.01). The number of TRAP-positive cells was significantly reduced as well (P<0.01). CONCLUSIONS: OR and its eggs could effectively suppress OVX-induced osteoporosis in rats, and increase bone turnover possibly by both an increase in osteoblastic activity and a decrease in osteoclastic activity. The present study provides evidence that OR and its eggs could be considered a complementary and alternative medicine for the treatment of postmenopausal osteoporosis.

The effect of clomiphene citrate on osteoporosis in ovariectomized rats.

OBJECTIVE: The aim of this study was to investigate whether clomiphene citrate (CC) administration could be a new therapeutic agent in case of contraindication of estrogen therapy for hormone-dependent osteoporosis and to show the changes in bone structure by histomorphometric analysis in ovariectomized rats administered CC. STUDY DESIGN: This study was carried out in the Experimental Surgery Laboratory of the Brain Research Centre of the Medical Faculty of Ege University. Four-month-old Sprague-Dawley rats were used for the experiment. The study was carried out on six groups of animals each consisted of eight rats. Four groups of rats were ovariectomized and 2 groups of rats were used as control group. For 6 weeks every day, rats were injected physiological saline solution (1 ml/kg), clomiphene citrate (1 or 10 mg/1 ml/kg, Organon), 17beta-estradiol (50 microg/1 ml/kg, within susame oil, Sigma) or susame oil (1 ml/kg, Sigma). Drug administrations were carried out according to the weekly weight measurements. Group 1(PSS), n = 8, non-ovariectomized, were injected with physiological saline solution. Group 2(CC-1), n = 7, non-ovariectomized, were injected with CC (1 mg/1 ml/kg). Group 3(OVX + CC-1), n = 7, ovariectomized, were injected with CC (1 mg/1 ml/kg). Group 4(OVX + CC-10), n = 6, ovariectomized, were injected with CC (10 mg/1 ml/kg). Group 5(OVX + E), n = 8, ovariectomized, were injected with 17beta-estradiol (50 microg/1 ml/kg). Group 6(OVX), n = 8, ovariectomized, were injected with susame oil (1 ml/kg) Bone-specific serum alkaline phosphatase (ALP) levels were measured and statistical analyses were made by Kruskal Wallis test. Left femur bone histomorphometric studies were done. The uteri were dissected out to measure their weight and ANOVA was used to show the intergroup differences. RESULTS: The level of ALP in group 3 was significantly higher than the other five groups. Bone histomorphometric examination showed that total bone volume in group 3, 4, and 5 was higher than group 6, and group 4 had the highest level of bone volume compared to the rest of the groups. Uterus weights in group 1 were significantly higher than group 3 and 6 (P = 0.02, P = 0.01) and uterus weights in group 5 were significantly higher than group 3 and 4 (P = 0.00, P = 0.01) CONCLUSIONS: In ovariectomized rats, treatment with CC is seen as effective as estrogen treatment in preventing osteoporosis, without causing uterin hyperstimulation. Nevertheless, further investigations on more rats are needed to assess whether it is an alternative treatment method to estrogen.

Comparative therapeutic use of Risedronate and Calcarea phosphorica--allopathy versus homeopathy--in bone repair in castrated rats.

Osteoporosis, a disease characterized by progressive bone loss, has been the target of several studies in the past few years. It results in a much higher risk for fractures and might cause slower bone lesion healing. The aim of this work was to study the effects of Risedronate (allopathic medicine) and Calcarea phosphorica 6CH (homeopathic medicine) on the repair of bone lesions in male rats with osteoporosis induced by castration. Eighty-four three-month-old rats were used divided into four groups of twenty-one animals each. Three groups where castrated and one group was submitted to Sham surgery. One month later, cortical lesions were made in all animals' tibiae and, after one day, the different experimental treatments began according to the following groups: CR--castrated/Risedronate (1 mg/kg/day); CCp--castrated/Calcarea phosphorica 6CH (3 drops/day); CP--castrated/placebo and SP--Sham/placebo. The animals were sacrificed at seven, fourteen and twenty-eight days after the beginning of the treatments and had their tibiae removed. Digital radiographs of the tibiae were taken and analyzed in order to evaluate the optical density of the defect area. Then, they were decalcified and processed for histological and histomorphometrical analysis. The data were submitted to ANOVA, and to the Tukey and Dunnett tests (5%). The allopathic and homeopathic treatments led to different bone formation as regards remodeling and maturation aspects. Further research is necessary to access the resistance and quality of the newly formed bone.

Estrogen replacement therapy.

The popularity of estrogen therapy for the menopausal woman seems to be on the rise again, with new evidence on the risks and treatment of osteoporosis and the protective effect of progestin on the endometrium becoming clearer. The risks of estrogen treatment must remain a prime concern of the practitioner, and hazards may be minimized through careful patient selection, education, examination, treatment, and follow-up. The resurgence of interest in the plight of the menopausal woman has stimulated an increasing number of competent investigators to attempt to solve the mysteries that until recently have been evaluated and treated by anecdote and homeopathic ministrations.

Comparative therapeutic use of Risedronate and Calcarea phosphorica - allopathy versus homeopathy - in bone repair in castrated rats / Comparação do uso terapêutico de Risedronato e Calcarea phosphorica - alopatia versus homeopatia - no reparo ósseo em ratos castrados

Osteoporosis, a disease characterized by progressive bone loss, has been the target of several studies in the past few years. It results in a much higher risk for fractures and might cause slower bone lesion healing. The aim of this work was to study the effects of Risedronate (allopathic medicine) and Calcarea phosphorica 6CH (homeopathic medicine) on the repair of bone lesions in male rats with osteoporosis induced by castration. Eighty-four three-month-old rats were used divided into four groups of twenty-one animals each. Three groups where castrated and one group was submitted to Sham surgery. One month later, cortical lesions were made in all animals' tibiae and, after one day, the different experimental treatments began according to the following groups: CR - castrated/Risedronate (1 mg/kg/day); CCp - castrated/Calcarea phosphorica 6CH (3 drops/day); CP - castrated/placebo and SP - Sham/placebo. The animals were sacrificed at seven, fourteen and twenty-eight days after the beginning of the treatments and had their tibiae removed. Digital radiographs of the tibiae were taken and analyzed in order to evaluate the optical density of the defect area. Then, they were decalcified and processed for histological and histomorphometrical analysis. The data were submitted to ANOVA, and to the Tukey and Dunnett tests (5 percent). The allopathic and homeopathic treatments led to different bone formation as regards remodeling and maturation aspects. Further research is necessary to access the resistance and quality of the newly formed bone.

A osteoporose, doença caracterizada pela perda de massa óssea, tem sido alvo de estudos nos últimos anos. Fraturas decorrentes da osteoporose são muito comuns e podem apresentar consolidação mais lenta. O objetivo deste trabalho foi avaliar o efeito do risedronato (medicamento alopático) e da Calcarea phosphorica 6CH (medicamento homeopático) no reparo de lesões ósseas em ratos com osteoporose induzida por castração. Para tanto, foram utilizados oitenta e quatro ratos, com três meses de idade, separados em quatro grupos de vinte e um animais, sendo três grupos submetidos à castração e um grupo a falsa cirurgia ("Sham"). Um mês após a cirurgia, foram realizadas lesões corticais na tíbia de todos os animais e, a partir do dia seguinte, os tratamentos experimentais foram iniciados de acordo com os seguintes grupos: CR - castrado/risedronato (1 mg/kg/dia); CCp - castrado/Calcarea phosphorica 6CH (três gotas/dia); CP - castrado/placebo e SP - "sham"/placebo. Os animais foram sacrificados aos sete, catorze e vinte e oito dias após o início do tratamento e as tíbias foram removidas. Radiografias digitais foram realizadas e avaliadas para obter a densidade óptica na área do defeito. Em seguida, foram descalcificadas e processadas para análise histológica e histomorfométrica. Os dados foram submetidos a ANOVA e aos testes de Tukey e Dunnett (5 por cento). Os tratamentos alopático e homeopático levaram a formação óssea de aspecto diferente considerando a remodelação e maturação. Mais pesquisas são necessárias para avaliar a resistência e qualidade do osso neoformado.