osteoprotegerin and Hyperparathyroidism

This review summarizes studies into the permissive role of T cells in the bone catabolic effects of hyperparathyroidism and parathyroid hormone (PTH).

Topics: Bone Resorption; CD4-Positive T-Lymphocytes; Humans; Hyperparathyroidism; Interleukin-17; Osteoclasts; Osteoprotegerin; Parathyroid Diseases; Parathyroid Hormone; RANK Ligand; T-Lymphocytes; Th17 Cells; Tumor Necrosis Factor-alpha

A narrow serum calcium level which is essential for many metabolic processes is regulated by the calcium-sensing receptor which regulates parathyroid hormone (PTH) release. Primary hyperparathyroidism is supposed to be the third most common endocrine disorder. Besides nephrolithiasis and an increased incidence of cardiovascular symptoms it is associated with bone loss and an increased risk of fracture. Several different classical bone turnover markers have been shown to be increased. However, there are many uncertainties in pathophysiology of PHPT. Hardly any conclusive data exist on the RANK (receptor activator of nuclear factor-kB)/RANKL (receptor activator of nuclear factor-kB ligand)/OPG (osteoprotegerin) system, cathepsin K, sclerostin, FGF-23 (Fibroblast growth factor-23), Klotho, and DKK 1 (Dickkopf 1) in patients suffering from PHPT.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone Morphogenetic Proteins; Bone Remodeling; Calcium; Cardiovascular Diseases; Cathepsin K; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Genetic Markers; Glucuronidase; Homeostasis; Humans; Hyperparathyroidism; Intercellular Signaling Peptides and Proteins; Kidney Calculi; Klotho Proteins; Osteoprotegerin; Parathyroid Glands; Parathyroid Hormone; Receptor Activator of Nuclear Factor-kappa B; Receptors, Calcium-Sensing

Topics: Animals; Arthritis, Rheumatoid; Bone Diseases, Metabolic; Bone Neoplasms; Carrier Proteins; Cytokines; Female; Glycoproteins; Humans; Hyperparathyroidism; Ligands; Male; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Osteitis Deformans; Osteoclasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Rats; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Intracortical porosities and marrow fibrosis are hallmarks of hyperparathyroidism and are present in bones of transgenic mice expressing constitutively active parathyroid hormone/parathyroid hormone-related protein receptors (PPR*Tg). Cortical porosity is the result of osteoclast activity; however, the etiology of marrow fibrosis is poorly understood. While osteoclast numbers and activity are regulated by osteoprotegerin (OPG), bisphosphonates suppress osteoclast activity but not osteoclast numbers. We therefore used OPG and bisphosphonates to evaluate the extent to which osteoclasts, as opposed to bone resorption, regulate marrow fibrosis in PPR*Tg mice after treatment of animals with vehicle, OPG, alendronate, or zoledronate. All three agents similarly increased trabecular bone volume in both PPR*Tg and control mice, suggesting that trabecular bone resorption was comparably suppressed by these agents. However, the number of trabecular osteoclasts was greatly decreased by OPG but not by either alendronate or zoledronate. Furthermore, intracortical porosity and marrow fibrosis were virtually abolished by OPG treatment, whereas alendronate and zoledronate only partially reduced these two parameters. The greater reductions in cortical porosity and increments in cortical bone mineral density with OPG in PPR*Tg mice were associated with greater improvements in bone strength. The differential effect of OPG versus bisphosphonates on marrow fibrosis, despite similar effects on trabecular bone volume, suggests that marrow fibrosis was related not only to bone resorption but also to the presence of osteoclasts.

Topics: Alendronate; Animals; Biomechanical Phenomena; Bone and Bones; Bone Resorption; Diphosphonates; Disease Models, Animal; Humans; Hyperparathyroidism; Imidazoles; Immunohistochemistry; Male; Mice; Mice, Transgenic; Osteoclasts; Osteoprotegerin; Porosity; Primary Myelofibrosis; Receptor, Parathyroid Hormone, Type 1; Tomography, X-Ray Computed; Zoledronic Acid

The skeleton is a major site of breast cancer metastases. High bone turnover increases risk of disease progression and death. However, there is no direct evidence that high bone turnover is causally associated with the establishment and progression of metastases. In this study, we investigate the effects of high bone turnover in a model of breast cancer growth in bone. Female nude mice commenced a diet containing normal (0.6%; 'Normal-Ca') or low (0.1%; 'Low-Ca') calcium content. Mice were concurrently treated with vehicle or osteoprotegerin (1 mg/kg/d s.c; n = 16 per group). Three days later (day 0), 50,000 Tx-SA cells (variant of MDA-MB-231 cells) were implanted by intratibial injection. On day 0, mice receiving Low-Ca had increased serum parathyroid hormone (PTH) and tartrate-resistant acid phosphatase 5b levels, indicating secondary hyperparathyroidism and high bone turnover, which was maintained until day 17. Osteoprotegerin increased serum PTH but profoundly reduced bone resorption. On day 17, in mice receiving Low-Ca alone, lytic lesion area, tumor area, and cancer cell proliferation increased by 43%, 24%, and 24%, respectively, compared with mice receiving Normal Ca (P < 0.01). Osteoprotegerin treatment completely inhibited lytic lesions, reduced tumor area, decreased cancer cell proliferation, and increased cancer cell apoptosis. Increased bone turnover, due to dietary calcium deficiency, promotes tumor growth in bone, independent of the action of PTH. Breast cancer patients frequently have low dietary calcium intake and high bone turnover. Treatment to correct calcium insufficiency and/or treatment with antiresorptive agents, such as osteoprotegerin, may be of benefit in the adjuvant as well as palliative setting.

Topics: Bone Neoplasms; Bone Resorption; Breast Neoplasms; Calcium; Calcium, Dietary; Cell Growth Processes; Cell Line, Tumor; Humans; Hyperparathyroidism; Osteoprotegerin; Parathyroid Hormone

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-kappaB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca(2+) diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca(2+) levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6-9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.

Topics: Absorptiometry, Photon; Animals; Carrier Proteins; Disease Models, Animal; Glycoproteins; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

The study found bone exchange disorder manifested by accelerated bone resorption, retarded bone formation, and the loss of the bone mineral density (BMD) of the axial and peripheral skeleton in 19 men (39 observations) 66 +/- 44 months following orthotopic heart transplantation (OTHT) and in 92 men 45 +/- 28 months after cadaveric kidney transplantation. An accelerated bone resorption, more pronounced in cadaveric kidney (CK) recipients, is associated with hyperparathyroidism (HPT) and renal dysfunction, while bone formation retardation is associated with a decrease in insulin-like growth factor-1 level. An increase in osteoprotegerin level is of compensatory character. The prominence of HPT depends on the degree of renal dysfunction; in CK recipients it also depends on the degree of the reduction in the levels of biologically active testosterone and estradiol. Reduction in BMD of the peripheral skeleton after OTHT are associated with the degree of renal dysfunction and a decrease in free testosterone index; after CK transplantation it is associated with HPT, the cumulative dose of glucocorticoids, reduction in the levels of biologically active testosterone and estradiol, as well as sex-hormone binding globulin (SHBG); reduction in spine BMD is only associated with SHBG.

Topics: Adult; Bone Density; Bone Diseases, Metabolic; Follow-Up Studies; Heart Transplantation; Humans; Hyperparathyroidism; Kidney Transplantation; Male; Osteoprotegerin; Postoperative Complications; Prognosis; Time Factors

The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) and ligand of receptor activator of NF-kappaB (RANKL) in human bone is incompletely understood. Most in vitro studies indicate that PTH decreases OPG and increases RANKL production. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Decreasing PTH levels by surgery normalizes bone metabolism, but the effects on skeletal OPG and RANKL production are unknown. In this study, 24 patients referred to our clinic for evaluation, and treatment of PHPT were included. A transiliac bone biopsy was done before (n = 24) and 12 months after parathyroidectomy (PTX) (n = 21). Biopsies were frozen in liquid nitrogen and RNA extracted using Trizol. A competitive RT-PCR assay for RANKL and OPG mRNA using artificial cDNA standards was developed and used for quantification. Results were normalized for GAPDH mRNA content. Before surgery, the RANKL/GAPDH gene expression ratio showed positive correlations with serum osteocalcin (r = 0.42, P < 0.05) and urinary NTX (r = 0.43, P < 0.05). The OPG/GAPDH mRNA levels in iliac bone before surgery correlated with serum osteocalcin (r = 0.52, P < 0.01), but not with bone resorption markers. The mRNA ratio of RANKL/OPG decreased significantly (P < 0.05) after surgery. In conclusion, RANKL and OPG gene expression within the human bone microenvironment are influenced by PTH, as the ratio RANKL/OPG decreased upon PTX. In addition, locally produced RANKL appears to affect bone turnover in the hyperparathyroid state.

Topics: Aged; Biomarkers; Bone and Bones; Bone Density; Bone Remodeling; Carrier Proteins; Cytokines; Female; Glycoproteins; Humans; Hyperparathyroidism; Male; Membrane Glycoproteins; Middle Aged; NF-kappa B; Osteoprotegerin; Parathyroid Hormone; Parathyroidectomy; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factor RelA

The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) remains controversial. Most in vitro studies indicate that PTH decreases OPG secretion by the osteoblast, but in vivo observations are conflicting. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Patients with PHPT are cured by surgery, resulting in normalization of PTH levels and bone metabolism, but the concomitant effects on OPG production are not known. The hypothesis of the present study was that the circulating level of OPG is diminished in patients with PHPT and increases with successful parathyroidectomy. We also speculated that serum OPG may determine the magnitude of bone loss up to the time of surgery. In the present study, 20 patients (17 women and 3 men, mean age 62 y) with PHPT who were candidates for surgical cure were examined before and 12 months after surgery. Bone turnover markers decreased and BMD increased significantly after surgery. Serum OPG did not correlate with PTH before surgery (r = 0.07, P = 0.77) and was not affected by parathyroidectomy (P = 0.79). After normalization of PTH, bone formation markers showed significant (P1NP) and near-significant (osteocalcin) correlations with serum OPG. In conclusion, serum OPG is not decreased in patients with PHPT, nor is serum OPG to any demonstrable extent regulated by PTH pre- or postoperatively.

Topics: Absorptiometry, Photon; Aged; Bone and Bones; Bone Density; Calcium; Female; Glycoproteins; Humans; Hyperparathyroidism; Ions; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Parathyroidectomy; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Numerous growth factors and cytokines are known to modulate bone turnover. An important, recently discovered complex involved in osteoclastogenesis is the osteoprotegerin/osteoprotegerin-ligand (OPG/OPGL) cytokine complex, which is produced by osteoblasts. Many factors, including parathyroid hormone (PTH), appear to affect bone turnover through this pathway. In this disorder, the role of the OPG/OPGL system in the pathogenesis of renal osteodystrophy, a disease with either low or high bone turnover, has not been investigated so far.. Thirty-nine chronic haemodialysis patients had bone biopsies, including histomorphometric and histodynamic examinations. In addition, the following serum biochemistry parameters were measured: serum OPG, intact PTH, PTH 1-84, total PTH, osteocalcin, total and bone alkaline phosphatases, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol.. On average, serum OPG levels were above the normal range. They were lower in adynamic bone disease (ABD) patients, than in patients with predominant hyperparathyroidism (HP) or mixed osteodystrophy (MO). Significant negative correlations were found between serum OPG and PTH levels, and between serum OPG and parameters of bone resorption (ES/BS) and bone formation (ObS/BS and BFR/BS) in HP and MO patients with PTH values < or =1000 pg/ml. For intact PTH levels < or =300 pg/ml, serum OPG was significantly lower in the group with ABD than in those with HP or MO (P<0.05).. In renal osteodystrophy the OPG/OPGL system is involved in the regulation of bone turnover induced by PTH. The determination of serum OPG levels could be of use in the diagnosis of low turnover bone disease, at least in association with PTH levels < or =300 pg/ml.

Topics: Aged; Bone and Bones; Bone Remodeling; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis