Background: Postmenopausal osteoporosis which results in a reduction of bone quality and bone density is one of the most prevalent diseases affecting people around the world. Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, the Odanacatib (ODN) developed by Merck & Co. is the only Phase III CatK inhibitor candidate with high efficacy in treating postmenopausal osteoporosis. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. In order to enhance the specificity of ODN to osteoclasts for suppression of bone resorption in postmenopausal osteoporosis, we have previously designed and synthesized (D-Asp8)-ODN conjugate by linking ODN with a promising osteoclast-targeted moiety D-Asp8. The data showed that D-Asp8 could facilitate the conjugated ODN specifically approaching osteoclasts, with reduced distribution in non-bone tissues, to inhibit the functional CatK activity within bone tissues in healthy rats. In this thesis, we hypothesized that the in vitro antiresorptive effects of (D-Asp8)-ODN conjugate were comparable with that of ODN. On the other hand, we also developed a QQQ-LC/MS method for quantitation of (D-Asp8)-ODN conjugate in plasma, which will be a valuable tool to support further pre-clinical studies. Aim: (1) To compare the antiresorptive effect between (D-Asp8)-ODN conjugate and ODN in vitro. (2) To develop and validate a practicable method for pharmacokinetic profile of (D-Asp8)-ODN conjugate in rats. Materials and Methods: The cytotoxic effect of (D-Asp8)-ODN conjugate and ODN were evaluated and compared by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effect of (D-Asp8)-ODN conjugate and ODN on Receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclasts formation and osteoclast function-related genes were evaluated and compared by Tartrate-resistant acid phosphatase (TRAP) staining and quantitative real time polymerase chain reaction (qRT-PCR). The effect of (D-Asp8)-ODN conjugate and ODN on osteoclast bone resorption activities were evaluated and compared by bone resorption pit assay. Moreover, the pharmacokinetic profile of (D-Asp8)-ODN conjugate in rat plasma was determined by using triple quadrupole liquid chromatography-mass spectrometry (QQQ-LC/MS) system. Result: The cytotoxicity of (D-Asp8)-ODN conjugate was significantly lower than that of ODN on the murine macrophage RAW 264.7 cell line. (D-Asp8)-ODN conjugate had no effect on RANKL-induced osteoclast formation, which was comparable with that of ODN. (D-Asp8)-ODN conjugate had no effect on the mRNA level of CTSK, but it could upregulate the mRNA levels of ACP5 and OSCAR, which was comparable with that of ODN. (D-Asp8)-ODN conjugate inhibited osteoclast bone resorption activity, which was comparable with that of ODN. The newly established QQQ-LC/MS protocol had good precision and accuracy for detecting (D-Asp8)-ODN conjugate in rat plasma. Finally, the pharmacokinetic profile of (D-Asp8)-ODN conjugate in rat plasma was determined. Following subcutaneous administration, the time to reach maximum concentration (Tmax) was 1.0 h, the antibiotics area under the concentration time-curves from time zero to infinity (AUC0-∞) was found to be 27.78 ug·mL-1·h and the terminal half-life (t½) was 1.4 h. Conclusion: (D-Asp8)-ODN conjugate had no effect on RANKL-induced osteoclast formation, which was comparable with ODN. The antiresorptive effect of (D-Asp8)-ODN conjugate was comparable with that of ODN. On the other hand, a new QQQ-LC/MS protocol has been established for the pharmacokinetic profile of (D-Asp8)-ODN conjugate in rat.

Osteoporosis is a systemic skeletal disease that affects millions of people worldwide. There are many possible etiologies for osteoporosis, including inherent variables like genetics and sex, and lifestyle variables like diet and exercise. Characterized by low bone mass and increased fracture risk, the disease places a burden on both the patients and the healthcare industry. Therefore, it is vital that research determine the mechanisms by which the risk factors affect BMD so that better diagnosis and treatment options may be developed. The purpose of this study was to examine the relationship between various osteoporosis risk factors and biochemical markers of osteogenic cell activity derived from bone-marrow MSCs. It was hypothesized postmenopausal white women, having the greatest risk for osteoporosis, would have elevated hydroxyproline and decreased ALP, indicative of greater bone resorption. Acetabular reamings were collected from 26 patients (15 males and 11 females) undergoing total hip arthroplasty at Boston Medical Center. MSCs from the reamings were plated and underwent osteoinduction into osteoblasts. The cells were then harvested and assayed for various indicators of cell growth and bone cell activity, such as DNA, ALP, and hydroxyproline. Our hypothesis was generally supported in that postmenopausal white women did have less ALP, an indicator of bone deposition, than premenopausal women and postmenopausal African American women. Additional findings and directions for future studies are further discussed in this paper.

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Orientador: Roberta Okamoto / Coorientador: Leonardo Perez Faverani / Banca: André Luís da Silva Fabris / Banca: Idelmo Rangel Garcia Júnior / Resumo: O presente projeto teve como proposta avaliar o processo de reparo ósseo na interface osso/implante em ratas submetidas à ovariectomia para a indução da deficiência de estrógeno e tratadas com fitoestrógeno genisteína (1mg/dia) por gavagem. Para isso, 30 ratas (Rattus novergicus albinus, Wistar), com peso médio de 200 gramas foram divididas em 3 grupos conforme a análise a que foram submetidas e o tratamento medicamentoso, sendo 10 ratas para o grupo SHAM SAL = Ratas submetidas à cirurgia fictícia, sem tratamento medicamentoso (gavagem com solução salina 0.9%); 10 ratas para o grupo OVX SAL = Ratas submetidas à ovariectomia bilateral, sem tratamento medicamentoso (gavagem com solução salina 0.9%); 10 ratas para o grupo OVX GEN = Ratas submetidas à ovariectomia bilateral, tratadas com fitoestrógeno genisteína (gavagem com 1mg/dia de genisteína). Foram utilizados 60 implantes, cada animal recebeu 2 implantes, sendo 1 em cada metáfise tibial. A eutanásia dos animais foi realizada após 60 dias da instalação dos implantes, por meio de sobredosagem anestésica. Para os grupo calcificados: nas análises por microtomografia computadorizada foram utilizadas as tíbias do lado direito de 6 ratas e para a análise da expressão gênica por PCR em tempo real, as 6 tíbias do lado esquerdo das mesmas ratas. Para a análise dos grupos descalcificados: 4 ratas foram submetidas à eutanásia na análise de imunoistoquímica osteoprotegerina - (OPG-SC21038), ativador do receptor nuclear kappa B ligante -... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The present project had as proposal to evaluate the process of bone repair in the bone / implant interface in rats submitted to ovariectomy for induction of estrogen deficiency and treated with phytoestrogen genistein (1mg / day) by gavage. For this, 30 rats (Rattus novergicus albinus, Wistar), with an average weight of 200 grams were divided into 3 groups according to an analysis and the drug treatment, being 10 rats for the group SHAM SAL = Rats submitted to the fictional surgery, without drug treatment (gavage with 0.9% saline solution); 10 rats for the OVX group SAL = Rats submitted to bilateral ovariectomy without drug treatment (gavage with 0.9% saline solution); 10 rats for the OVX group GEN = Rats subjected to bilateral ovariectomy, treated with phytoestrogen genistein (gavage with 1mg / day of genistein). 60 implants were installed, with 2 implants in each animal. The euthanasia of the animals was performed 60 days after implant's installation, by anesthetic overdose. The calcified groups analysis with computerized microtomography was peformed in right tibiae of 6 rats and the gene expression analysis by PCR was performed in left tíbia of the same animals. For the decalcified analysis through immunolabeling experiments, 4 rats were submited to eutanásia in order to evaluate the presence of Osteoprotegerin (OPG - SC21038), activator of nuclear kappa B ligand (RANKL - SC7627), Osteocalcin (OC - SC 18319), and acid resistant phosphatase tartaric acid (TRAP - SC 30832) ... (Complete abstract click electronic access below) / Mestre

El objetivo fue determinar la densidad de masa ósea en pacientes con fractura de Colles y los principales factores de riesgo para esta fractura en mujeres postmenopaúsicas en el hospital Arzobispo Loayza entre el 1° de marzo del 2002 y el 30 de abril del año 2003. Se comparó mujeres postmenopaúsicas con fractura de Colles atendidas en el consultorio de ortopedia y traumatología con mujeres postmenopaúsicas sin fractura, correspondiendo 26 casos y 30 controles. A todas se les midió la densidad ósea del antebrazo contralateral, cadera y columna. La incidencia de fractura de Colles fue 1,6 por 100 pacientes. La edad, talla y peso medios en pacientes con fractura de Colles fue 64,0 +/- 7,0 años, 1,53 +/- 0,06 metros y 58,2 +/- 6,1 kilogramos; respectivamente. En estas pacientes, la media del valor T en la muñeca contralateral, columna y cadera fue –2,84 +/- 0,8, - 3,2 +/- 0, 7 y –1,87 +/- 0,8; respectivamente, y la prevalencia de osteopenia y osteoporosis fue 26,9% y 69,2%; respectivamente. El valor T de la muñeca contralateral fue un factor de riesgo independiente para fractura de Colles (OR = 1,5; intervalo de confianza al 95%: 1,2 – 1,9). La edad, peso e índice de masa corporal no se correlacionaron con la fractura de Colles. La edad como variable categórica (≤ 65 años y > 65años) se asoció con osteoporosis. Se concluyó que la osteoporosis fue más prevalente en mujeres postmenopaúsicas con fractura de Colles, el valor T de la muñeca contralateral fue un factor de riesgo independiente de fractura de Colles, y el riesgo de fractura se incrementó con la edad. / --- The objective was to determine the bone masss in patiens with Colles, Fracture and the mains factors of risk in post menopause women in Loayza Arzobispo Hospital during 1°March 2002 and 30 April 2003. It compare post menopause women Colles, Fracture and without, orthopaedic traumatology, s consult; 26 cases and 30 controls respectively,all was measure bone masss forearm,hip an spine. The incidence of Colles, Fracture were 1.6/100 patients. The age,stature and weight middle were 6,4 o +/- 7.0 years,1.53 +/- 0.06 mt and 58.2% +/-6,1 kg respectivaly. These patients the middle value T in the opposite wrist,spine and hip were - 2,04 +/- 0,8, -3.2 +/- 0,7 and –1,87 +/- 0,8 respectively and the osteopeny and osteoporosis prevalence were 26,9 and 69,2 respectively. The value T in the opposite wrist was a independent risk factor in the Colles, Fracture (OR=1,5 confidence interval corporal 95%: 1.2-1.9).the age, weigth, corporal mass index haven;nt correlation with Colles, Fracture.the age was a variable associative with osteoporosis. The conclusions is the osteoporosi was more prevalence in menopause women with Colles, Fracture,the opposite wrist value T was a risk factor independece respect Colles, Fracture and the fracture risk incremence with the age. / Tesis de segunda especialidad

Introduction: Osteoporosis is a chronical systemic metabolic disease of bone tissue, which is manifested by a decrease in the amount of bone mass and/or a decrease in its quality and may result in a fracture. Fractures are also common for primary hyperparathyroidism due to increased parathyroid hormone secretion. Surgical treatment will help increase bone density in most cases, nevertheless emphasis is placed on reducing risk factors for osteoporosis and fractures. Objective: Purpose of this thesis is to map the nutrition condition with focus on calcium and protein intake of postmenopausal women after successful surgical intervention for primary hyperparathyroidism (PHPT group), and to evaluate the results in relation with osteoporosis and fractures. Methods: Nutritional status was assessed using questionnaires of eating habits and analysis of three-day menus. Intakes of energy, protein, fat, sugar, fiber, free sugar, vitamin C, sodium, calcium nad phosphorus intake were calculated using Nutriservis PROFI program (and other nutritional databases). The degree of vitamin D saturation was obtained from serum calcidiol concentrations. Body composition and bone mineral density parametres were measured using dual energy X-ray absorptiometry. Results: Nutritional analysis of diets showed no statically...

Vitamin D and calcium are essential for the health of the elderly population. Due to the changes that occur in the body during aging, it is necessary to monitor the intake of these micronutrients and, if necessary, to supplement or substitute them appropriately. This thesis focuses on prevention of vitamin D and calcium deficiency in old age. The theoretical part explains the function of vitamin D and calcium in the human body, their metabolism, sources and problems of deficiency or excess. There is information about diseases related to the deficiency, especially osteoporosis and sarcopenia. The practical part has two sections. The first analyses the data from the SPRINTT trial. Data related to vitamin D, calcium, their supplementation and sarcopenia, as a disease associated with vitamin D deficiency, were used. The second section analyzes the data from a questionnaire survey in nursing homes, which obtained information about the health of seniors, the frequency of consumption of selected foods and vitamin D and calcium supplementation. Using data from the SPRINTT, it was found that 55 % of men and 40 % of women had the values of sarcopenia. 11 % of the participants had vitamin D deficiency. The data from the questionnaire found that only 51 % of respondents over the age of 70 supplemented with...

Background: Osteoporosis has become a major problem worldwide as the population ages. An osteoporotic fracture is associated with a high rate of morbidity and mortality. Data on the prevalence, risk factors and outcome of osteoporotic fractures in South Africa remains sparse. Method: A retrospective audit was undertaken in all patients attending the Endocrine Clinic at Groote Schuur Hospital between March 2019 and March 2020 for the treatment of osteoporosis. Patients folders were reviewed to obtain the following information: demographic data, risk factors, laboratory investigations, treatment, baseline and follow up DEXA scans. Results: 264 patients were evaluated, average age 65.7 ± 12.3 years, 92.8% (n=245) were female. Common risk factors included smoking (50.8%, n=134), vitamin D deficiency (29.2%, n=77), steroid use (21.6%, n=57) and primary hyperparathyroidism (15.2%, n=40). A fragility fracture was diagnosed in 68.6% (n=181) - vertebral only (54.7%, n=99), hip only (14.9%, n=27), vertebral and hip (10.5%, n=19), wrist (7.2%, n=13) and other (12.7%, n=23). Bisphosphonates were used by 75% (n=198) of patients at the time of enrolment. Of these, 80.8% (n=160) received intravenous zoledonic acid alone, 6.1% (n=12) received oral alendronate alone and 13.1% (n=26) initially received alendronate followed by intravenous zoledronic acid. Over 5.2 years there was an improvement in bone mineral density (BMD) of 4.4% at the lumbar spine, while there was slight worsening of BMD at the femoral neck (- 0.17%). A fracture whilst on treatment occurred in 10.6% (n=21) of patients. Conclusion: The majority of patients with osteoporosis at Groote Schuur Hospital had a fragility fracture at diagnosis with a vertebral fracture being most common. Bisphosphonate treatment showed a measurable improvement in BMD at the lumbar spine, however, there was no improvement at the femoral neck. Despite this, few patients had a symptomatic vertebral or hip fracture whilst on treatment.

The availability of a once-a-year zoledronic acid infusion heralds a new era in the management of osteoporosis. It virtually eliminates the problem of poor compliance with orally administered bisphosphonates and, because it bypasses the gastrointestinal tract, it is not associated with gastrointestinal side effects. Zoledronic acid is effective for the treatment and prevention of postmenopausal osteoporosis, and for the treatment of osteoporosis in men, and glucocorticoid- induced osteoporosis. When administered within three months of a hip fracture, it reduces mortality and the risk of subsequent fractures. It is remarkably free of serious adverse effects. After administration of the intravenous infusion, about 18% of bisphosphonate-naïve patients experience an acute-phase reaction, including low-grade temperature, aches, and pains. This is reduced to about 9% in those who have been treated with oral bisphosphonates, and is further reduced by the concomitant and subsequent administration of acetaminophen. The likelihood and magnitude of the acute-phase reaction is less after the second infusion. Other adverse effects are similar to those encountered with other bisphosphonates. Because it is mostly excreted by the kidneys, zoledronic acid should not be administered to patients with a creatinine clearance less than 35 mL/min. It should not be administered to patients with hypocalcemia.

To compare the efficacy and safety of nandrolone decanoate and calcium (NDC) with those of calcium alone (CAL) in men with idiopathic osteoporosis, a 12-month, randomized, prospective, controlled study, was performed in an outpatient clinic. Twenty-one men with idiopathic osteoporosis (as determined by radiological and dual energy x-ray absorptiometry findings) were randomly allocated to either 50 mg nandrolone decanoate intramuscularly (im) weekly and 1,000 mg oral calcium carbonate daily (NDC group) or to 1,000 mg oral calcium carbonate daily (CAL group). Bone densitometry (total body, left femur, and lumbar spine), serum, and urine biochemical parameters were measured at 3-month intervals. In the NDC group, bone mineral density initially increased, reached a plateau, and then decreased to near baseline levels at 12 months. Increases in lean muscle mass mirrored these changes. Free and total testosterone significantly decreased. Hemoglobin increased in all patients in this group. Patients in the CAL group exhibited no significant change in either total body or bone mineral density or biochemical parameters. Thus, nandrolone decanoate, 50 mg im weekly, transiently increases the bone mass of men with idiopathic osteoporosis in this preliminary study. Careful monitoring is necessary.