Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Figure 7 summarizes the heritable disorders identified to date that directly involve the RANKL/OPG/RANK signaling pathway in humans. Activating mutations in TNFRSF11A encoding RANK and deactivating mutations in TNFRSF11B encoding OPG cause systemic bone disease (FEO, PDB2, ESH and JPD) featuring accelerated bone turnover, low bone mass, deafness early in life, and loss of dentition by enhancing signaling. No human disease has been identified involving defects in the TNFSF11 gene encoding RANKL. Despite genetic bases for these autosomal dominant and recessive conditions involving bone cell receptors, focal expansile osteolytic lesions are common and can occur perhaps from further local activation of osteoclast-mediated bone resorption following trauma. These disorders resemble PDB which can be inherited as an autosomal dominant trait with focal osteolytic disease, sometimes with deafness and tooth loss, and increasingly associated with mutations, but in other genes.
J Musculoskelet Neuronal Interact 2004 Sep
PMID:Heritable disorders of the RANKL/OPG/RANK signaling pathway. 1561 93

The OPG/RANKL/RANK cytokine system is essential for osteoclast biology. Various studies suggest that human metabolic bone diseases are related to alterations of this system. Here we summarize OPG/RANKL/RANK abnormalities in different forms of osteoporoses and hyperparathyroidism. Skeletal estrogen agonists (including 17beta-estradiol, raloxifene, and genistein) induce osteoblastic OPG production through estrogen receptor-alpha activation in vitro, while immune cells appear to over-express RANKL in estrogen deficiency in vivo. Of note, OPG administration can prevent bone loss associated with estrogen deficiency as observed in both animal models and a small clinical study. Glucocorticoids and immunosuppressants concurrently up-regulate RANKL and suppress OPG in osteoblastic cells in vitro, and glucocorticoids are among the most powerful drugs to suppress OPG serum levels in vivo. As for mechanisms of immobilization-induced bone loss, it appears that mechanical strain inhibits RANKL production through the ERK 1/2 MAP kinase pathway and up-regulates OPG production in vitro. Hence, lack of mechanical strainduring immobilization may favor an enhanced RANKL-to-OPG ratio leading to increased bone loss. As for hyperparathyroidism, chronic PTH exposure concurrently enhances RANKL production and suppresses OPG secretion through activation of osteoblastic protein kinase A in vitro which would favour increased osteoclastic activity. In sum, the capacity for OPG to antagonize the increases in bone loss seen in many rodent models of metabolic bone disease implicates RANKL/OPG imbalances as the likely etiology and supports the potential role for a RANKL antagonist as a therapeutic intervention in these settings.
J Musculoskelet Neuronal Interact 2004 Sep
PMID:The OPG/RANKL/RANK system in metabolic bone diseases. 1561 94

This manuscript reviews the theories behind the propensity of prostate cancer to cause bone metastases and skeletal implications of the prostate cancer biology and treatment modalities. The escape of tumor cells from the primary tumor in the prostate to secondary tumor sites in the axial skeleton probably occurs before the primary tumor is detected. Several theories offer explanations for the observed proclivity of prostate tumors to selectively colonize the axial skeleton. The interaction between the tumor cells and cells that populate bone marrow, in particular osteoblasts and osteoclasts, is important for creating a 'fertile' environment where tumor cells can establish and grow. Prostate cancer cells are capable of producing growth factors that can affect both osteoblasts, resulting in osteoblastic bone formation, and osteoclasts, resulting in excessive bone resorption. In addition to the capability to progress from testosterone-dependent to testosterone-independent phenotype, the hallmark of metastatic prostate cancer is osteosclerosis similar to one induced experimentally in nude rats using CWR22 human prostate cancer cell line. Metastatic bone disease caused by excessive bone formation and bone resorption is the major cause of morbidity in patients with prostate cancer. The most common symptoms include pain, pathological fractures, spinal cord compression, cranial nerve palsies, bone marrow suppression and hypercalcemia. The introduction of prostate-specific antigen in clinical practice created a shift to where more prostate cancer patients with early disease receive androgen ablation treatment, which in return causes more bone loss and cancer-associated osteoporosis. Introduction of third generation bisphosphonates to treat skeletal consequences of malignancy further stressed the important interaction between the bone marrow stroma and cancer cells. Nevertheless, animal models and human prostate tumor cell lines that mimic all aspects of skeletal conditions in prostate cancer patients including osteoblastic bone response are needed to develop and screen for novel therapeutic and diagnostic modalities.
J Musculoskelet Neuronal Interact 2003 Jun
PMID:Skeletal implications of prostate cancer. 1575 51

In 1997 Professor J. Gorski suggested endocrinology needed new paradigms (Endocrine News 1997; 22:4,12). 'Connecting the dots' between diverse facts and ideas drawn from many lines of inquiry, plus accumulating evidence and increasing inadequacies of earlier ideas and terminology, led to an updated bone physiology called the 'Utah paradigm' that reveals new genetic and hormonal potential roles in bone physiology and disorders. One way to find a bone disorder's cause(s) and treatment( s) could depend on understanding the underlying physiology well enough to design effective drugs for it. In early views cell-level effects on osteoblasts and osteoclasts could explain most endocrine and genetic roles in bone disorders. The updated bone physiology supplements those views with roles of bone's tissue-level 'nephron-equivalent' mechanisms (NEMs) and their functions (NEFs), including some roles of biomechanics, whole-bone strength and muscle strength. That updated physiology reveals at least 42 nexuses above the cell level, some of them extraosseous, where genetic and/or hormonal effects might cause or help to treat varied bone problems. That multifactorial physiology also suggests that in vivo skeletal phenomena usually depend on many interlocking, laddered and nested feedback systems. Due to lack of study, how genes and hormones affect those nexuses and feedback systems still remains nearly unknown. Because studies of bone physiology in in vitro systems seldom if ever correctly predicted the in vivo effects, further live-animal research should seek the in vivo effects. This article suggests why more of that kind of research is needed, and some directions it could take.
J Musculoskelet Neuronal Interact 2003 Jun
PMID:Perspective: genetic and hormonal roles in bone disorders: insights of an updated bone physiology. 1575 52

Thirty male adult Wistar rats (300-/+10 g body weight) underwent either 5/6 nephrectomy (Nx, n=20) or sham operation (SHAM, n=10) to determine olpadronate effects in an experimental model of uremic bone disease. For a 38-day period, 10 rats received olpadronate (16microg/100g bw) once a week (Nx+OPD) and the other vehicle (Nx). SHAM received vehicle. At baseline, treatment onset (t=7 days) and end of study (t=45 days) calcium, phosphorus, creatinine, bone alkaline phosphatase (b-ALP) and deoxypyridinoline crosslinks (DPyr) were determined. At t=0 and t=45 bone mineral density (BMD) was measured by DXA. At t=45 the right tibia was removed for bone histology. There were no differences in serum calcium. Phosphorus increased in Nx and Nx+OPD compared to SHAM (p<lt 0.05). The b-ALP increased from t=0 to t=7 in Nx and Nx+OPD (p<0.05) and decreased thereafter to SHAM levels. DPyr/creat increased in Nx compared to SHAM (p<0.05) and Nx+OPD (p<0.001). Nx+OPD presented lower DPyr excretion than SHAM rats (p<0.01). At t=45, tibia BMD of Nx was 20% and 26% lower than in SHAM (p<0.005) and Nx+OPD, respectively, (p<0.001). BMD was higher Nx+OPD than in SHAM (p<0.05). OPD prevented the loss of bone volume, the increment in osteoid volume and erosion surface observed in Nx group (p<0.05). OPD also prevent the increment in the number of osteoclasts (OC) and the active OC surface and decreases the number of TRAP(+)-OC (p<0.05). In summary, OLP may be beneficial in osteopenia associated to high turnover bone disease of CRF. However, the use of bisphosphonate therapy for renal insufficiency must be further investigated in order to clarify essential aspects of treatment as the patient selection and several aspects of treatment, such as optimum dose, frequency, and safe period of administration.
J Musculoskelet Neuronal Interact 2005 Jun
PMID:Changes in bone volume and bone resorption by olpadronate treatment in an experimental model of uremic bone disease. 1595 35

Osteoporosis is the most prevalent metabolic bone disease and a major clinical and public health problem. Heredity plays an important and well-established role in determining the lifetime risk of this disease. Major efforts are currently underway to identify the specific genes and their allelic variations that contribute to the heritable component to osteoporosis. A number of laboratories are using quantitative trait locus (QTL) methods of genome scanning in families and animal models to identify candidate genomic regions and, ultimately, the genes and genetic variations that lead to osteoporosis. Several chromosomal regions of the human genome have now been linked to osteoporosis-related phenotypes. Although the specific genes contributing to the majority of these linkage signals have not been identified, two positional candidate genes have now been identified: low density lipoprotein receptor-related protein 5 (LRP5) and bone morphogenetic protein 2 (BMP2). A number of QTL has also been identified by cross-breeding strains of mice with variable bone density and several of these QTL have been fine mapped, providing a rich new base for understanding osteoporosis. Genetic association analyses have also provided evidence for a modest relationship between allelic variants in several biological candidate genes and bone mass and the risk of fracture. These ongoing animal and human studies will provide a continuing source of new insight into the genetic regulation of bone and mineral metabolism and the molecular etiology of osteoporosis. The new insight that will emerge from this ongoing research should lead to new ways of diagnosing, preventing and treating the growing clinical and public health problem of osteoporosis.
J Musculoskelet Neuronal Interact
PMID:The search for human osteoporosis genes. 1667 85

Bisphosphonates (formerly termed diphosphonates) were first synthesized in the late 1800s; however, their clinical use has been relatively recent. The bisphosphonates' affinity for hydroxyapatite crystal surface led Procter and Gamble to test these compounds in dental, then medical applications. With key input from university researchers, this led to the medical use of the first bisphosphonate, etidronate disodium in 1968 to treat a young patient with myositis ossificans progressiva. Further clinical research led to widespread medical application for the bisphosphonate class including use as a diagnostic in radionuclide bone imaging agents, treatment of osteoporosis, Paget's disease of bone, hypercalcemia of malignancy and metastatic bone disease. The historical development of bisphosphonates provides an excellent example of how observations and knowledge obtained at the basic science level were applied and successfully tested in the clinic. The end result of these efforts has provided health care professionals with diagnostic and therapeutic tools to improve the lives of patients.
J Musculoskelet Neuronal Interact
PMID:Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. 1739

The purpose of the study was to validate optical segment tracking, a new method for in vivo human tibia deformation measurements and to assess bending in a three-point bending test. The approach relies upon optical motion capturing of reflecting marker clusters affixed to the bone via screws inserted three millimeters into the corticalis in local anesthesia. The method was tested in five healthy subjects. Screws were left in place for six to eight hours and a variety of exercises performed. A pain questionnaire was used to assess pain levels. PQCT-images were taken to locate screw holes in the bone. A three-point bending test was performed and repeatability evaluated. The new method shows good feasibility though this was previously considered impossible by many experts. Local anesthesia works for screw implantation and explantation. Results show linearity with an average of 0.25 degrees per 10 kg of weight applied with good repeatability (average variation coefficient 8%). Optical segment tracking is feasible for human in vivo bone deformation measurements. There is a variety of possible clinical and experimental applications including stability testing of osteosyntheses and joints, monitoring of bone healing, evaluation of exercises in physiotherapy, and assessment of bone deformation patterns in bone disease.
J Musculoskelet Neuronal Interact 2014 Mar
PMID:In vivo measurements of human bone deformation using optical segment tracking: surgical approach and validation in a three-point bending test. 2487 30

There are numerous studies presenting the beneficial effect of bisphosphonates (BPs) on bone disease of patients suffering from beta-thalassemia major (TM). Although BPs have been widely used, adverse events have been described including atypical femoral fractures (AFF). In the present case, a male adult patient suffering from TM sustained an AFF fulfilling all major and two minor criteria. Before AFF, the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy. To our knowledge, this is the first reported case of AFF in a patient suffering from TM, probably due to the small sample size of patients with thalassemia. The purpose of the present case is to increase the awareness amongst haematologists, who mainly deal with TM patients, of the adverse events of BP use.
J Musculoskelet Neuronal Interact 2016 Mar
PMID:Atypical femoral fracture in a beta-thalassemia major patient with previous bisphosphonate use: case report and a review of the literature. 2694 26