Metabolic bone- Associated Diseases

Vinod Naneria

Choithram Hospital & Research Centre

Indore, India

Associated diseases

• Obesity

• Type 2 DM

• Ca prostrate

• Hypercalcemia

• Multiple myeloma

• Metastatic bone diseases

• Hypothyroidism

• Myocardial diseases

Obesity• M/F ratio of Coronary artery disease: 4 / 1

• Peripheral vascular calcification ↑ F

• M/F ratio of Hypothyroidism 1/10

• F/M average age: F 3 years > M

• Peri-menopausal Hypothyroidism ↑ body weight.

• Obesity increases Bone mineral mass

• Extra production of Estrogen by adipose tissues

• Hyperthyroid causes Osteoporosis.

Obesity and Osteoporosis• Extensive epidemiological data show that high

body weight or BMI is correlated with high bone mass, and that reductions in body weight may cause bone loss .

• Larger body mass imposes a greater mechanical loading on bone, and that bone mass increases to accommodate the greater load.

• Adipocytes are important sources of estrogen production in postmenopausal women, and estrogen is known to inhibit bone resorption by osteoclasts.

Obesity and Osteoporosis• Obesity has been associated with Insulin resistance,

characterized by high plasma levels of insulin. • High plasma Insulin levels may contribute to a variety

of abnormalities, including androgen and estrogen overproduction in the ovary, and reduced production of sex hormone-binding globulin by the liver.

• These changes may result in elevated sex hormone levels, leading to increased bone mass due to reduced osteoclast activity and possibly increased osteoblast activity .

Leptin – as Hormone

• Leptin (from the Greek word for "thin"), Leptin is certainly one of the energy monitors in humans.

• The first studies on Leptin were done on mice. It was discovered that Leptin is the animal's "fat-o-stat" -- that is, its " satiety hormone" -- and it tells the animal when to stop eating or to lapse into an energy-conserving torpor when food is lacking.

• Because Leptin is made by white fat cells, its concentration in the blood varies with the fat load, which it limits by reducing the secretion of a hypothalamic eating stimulator, neuropeptide Y (NPY).

• Leptin, discovered in mice in 1994, is the product of the estrogen-dependent Ob(Lep) gene, located on the mouse chromosome 6.

• In humans, this gene is located on chromosome 7q31.3. • Leptin is a 16-kDa protein that can bind to 6 types of receptor -- LepRa to

LepRf -- with LepRb, the so-called "long receptor," being the only one able to send a complete signal.

Adipose tissue - Leptin Intracerebroventricular

but not intravenous leptin decreases bone formation. This finding is consistent with the observations that obesity protects against bone loss and that most obese humans are resistant to the effects of leptin on appetite. Thus, there may be neuroendocrine regulation of bone mass via leptin.

Leptin, is a 16 kDa protein derived from white fat cells. It regulates the size of the body’s fat load (i.e., energy reserves)

other functions: bone growth. The evidence so far indicates that leptin controls bone growth in two ways. It stimulates the release of an undefined hypothalamic osteoblast-inhibiting factor(s), which limits the amount of bone matrix that osteoblasts can make.

Leptin is a bone anabolic factor that directly stimulates bone growth by inducing osteoblasts to make IGF-I (insulin-like growth factor-I) and inhibiting osteoclast generation.

Leptin indirectly restrains but directly stimulates bone formation. Leptin from fat cells or from late-stage, matrix-mineralizing osteoblasts inhibits osteoclast generation by stimulating the production of the anti-osteoclastogenic osteoprotegerin (OPG) and reciprocally reducing the pro-osteoclastogenesis RANK by marrow osteoblastic cells.

Leptin also causes osteoblastic cells to make IGF-I and TGF-betas, which in turn stimulate the proliferation of osteoprogenitor cells (osteoprogenitor), stimulate bone matrix mineralization, and prevent osteoblasts and osteocytes from committing apoptotic suicide.

Leptin also stimulates hypothalamus cells to make some kind of hypothalamic osteoblast inhibitory factor (HOBIF) or trigger some neural process that restrains osteoblasts' matrix-making activity.

Leptin

Leptin inhibits the release of neuropeptide Y (NPY), which prevents the activation of Y2R receptors, signals that would otherwise mimic HOBIF's osteoblast-restraining activity.

But, if Leptin -- and with it, HOBIF production -- should decrease, NPY production would surge, and the osteoclast-suppressing signals from Y2R receptors would take over from HOBIF. However, according to the experience so far with rodents, injecting leptin can override the inhibitory brain-based mechanisms and directly stimulate bone formation.

Leptin drives ovarian cycling by stimulating the secretion of gonadotropin-releasing hormone (GnRH) and thus follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release.

Therefore, the lack of Leptin and the consequent estrogen shortage in obese Ob(Lep)-/- mice should cause bone loss because of a normally estrogen-suppressed population explosion of bone-destroying osteoclasts, similar to what occurs in the bones of ovariectomized rodents, ovariectomized monkeys, and postmenopausal women.

Leptin

The Bone-Related Pieces of the Leptin Puzzle

Both Ob(Lep)-/- mice without leptin, as well as Db-/- mice with disabled LepRb receptors that can make leptin but can't respond to it, have an abnormally high bone mass that appears before the animals start loading up with fat and is therefore not just a trivial consequence of bones adjusting to increased body weight.

The high bone mass in thin A-ZIP/F-I mice that do not have leptin-making white fat cells provides proof that it is a lack of leptin, and not excessive weight, that is responsible for high bone mass.

The high bone mass is not, due to more osteoblasts being generated to face the osteoclast onslaught. Only a normal number of osteoblasts are available to face the osteoclasts.

These are super-osteoblasts that can make twice as much matrix as normal osteoblasts. Injecting leptin intracerebrally causes the bones of Ob(Lep)-/- mice to lose mass; thus, it seems that leptin restrains osteoblast activity by stimulating the production of some kind of hypothalamic osteoblast inhibitory factor (HOBIF) or neural process. Thus was found the first of the bone-related pieces of the leptin puzzle.

Obese (fa/fa) Zuker rats, like Ob(Lep)-/- mice, cannot make leptin and also have supernormal bone mass, which probably means that rats have the same leptin-dependent, brain-based, osteoblast-restraining mechanism as mice.On the other hand, the direct responses of rat bone cells and bones to injected leptin are unequivocally positive or anabolic. Primary rat osteoblasts and ROS 17/2.8 osteoblastic osteosarcoma cells have LepRb receptors.

And intraperitoneally infused recombinant human leptin in tail-suspended rats prevents the reduction of tibial metaphyseal trabecular bone BMD resulting from hind limb disuse (ie, the lack of normal bone-maintaining strain pulses produced by the hind limbs of tail-suspended rats), and it actually increases femoral diaphyseal bone BMD in the tail-suspended rats. Leptin has also been found to reduce ovariectomy-induced bone loss in rats.

Incidentally, this observation suggests that leptin might eventually be used to prevent the loss of bone in astronauts during long voyages in space.

Leptin

• Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance.

• The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts.

• Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked.

• The emerging importance of the bone–fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures.

Energy Balancing and Skeletal Health

Three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: • leptin, • peroxisome proliferator-activated receptor gamma• osteocalcin pathways.

Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.

Energy Balancing and Skeletal Health

• Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts.

• Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone–fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures.

• Adipocytes are derived from a mesenchymal precursor stem cell that also gives rise to osteoblasts, chondroblasts, myoblasts, and fibroblasts.

• An osteoblast can be transformed to an adipocyte if Pparγ2 (peroxisome proliferator-activated receptor γ2) is expressed, while an adipocyte can be converted to an osteoblast if Runx2 is expressed.

Fat cell targets for skeletal health

BMD + Type 2 DM Rx Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator-activated

receptor gamma (PPARgamma) nuclear transcription factor.

Rosiglitazone and Pioglitazone, are commonly used in the management of type II diabetes mellitus, and play emerging roles in the treatment of other clinical conditions characterized by insulin resistance.

Over the past decade, a consistent body of in vitro and animal studies has demonstrated that PPARgamma signaling regulates the fate of pluripotent mesenchymal cells, favoring adipogenesis over osteoblastogenesis.

In the past year, however, several clinical studies have reported adverse skeletal actions of TZDs in humans. Collectively, these investigations have demonstrated that the TZDs currently in clinical use decrease bone formation and accelerate bone loss in healthy and insulin-resistant individuals, and increase the risk of fractures in the appendicular skeleton in women with type II diabetes mellitus. These observations should prompt clinicians to evaluate fracture risk in patients for whom TZD therapy is being considered, and initiate skeletal protection in at-risk individuals.

Research over the past two years has provided new clinical evidence that the currently prescribed TZDs increase fracture risk and bone loss, at least in women. Combined with the findings from rodent and in vitro models, these clinical results suggest that activation of PPAR  can play a role in bone loss. With the widespread use of TZDs as a diabetes treatment, further research is needed to delineate the groups that are most susceptible to TZD-induced osteoporosis, to determine the rate of bone loss with TZD treatment beyond 16 weeks, to assess the effects of TZDs on marrow adiposity, cortical and trabecular bones, and to identify treatments to prevent TZD-induced fracture risk. Addressing these questions will advance our ability to prevent TZD-induced osteoporosis and will provide a better understanding of the role of PPAR  activation in bone metabolism.

BMD + Type 2 DM Rx

• The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women.

• Thiazolidinediones, which are peroxisome proliferator-activated receptor-gamma agonists, are widely prescribed to patients with disorders characterized by insulin resistance.

• Preclinical studies suggest that peroxisome proliferator-activated receptor-gamma signaling negatively regulates bone formation and bone density. Human data on the skeletal effects of thiazolidinediones are currently available only from observational studies.

• Short-term therapy with rosiglitazone exerts detrimental skeletal effects by inhibiting bone formation. Skeletal end points should be included in future long-term studies of thiazolidinedione use.

:  J Clin Endocrinol Metab. 2007 Apr;92(4):1305-10. Epub 2007 Jan 30.  Links Comment in: J Clin Endocrinol Metab. 2007 Apr;92(4):1232-4. Nat Clin Pract Endocrinol Metab. 2007

Sep;3(9):622-3. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. Department of Medicine, University of Auckland, and LabPlus, Auckland City Hospital, New Zealand.

a.grey@auckland.ac.nz

BMD + Type 2 DM Rx

Associations between coronary disease and serum OPG and RANKL levels

Vascular calcification is a pathological sequence of events that has similarities to the normal physiological process of osteogenesis.1,2 It is thought to result from an imbalance in both local and systemic inhibitors and promoters,3,4 which occurs as a consequence of chronic inflammation, hyperleptinemia, and a deregulation of various bone-regulating proteins. It is common in patients with diabetes and renal failure and in the elderly.4,5 The fact that coronary artery calcification is such a major health problem and the recognition that it is highly correlative  with mortality risk6 makes the understanding of vascular calcification a worthy and exciting area of study.

 In normal skeletal physiology, bone deposition by osteoblasts is in balance with bone resorption by osteoclasts. RANKL (receptor activator of nuclear factor [NF]- B ligand) and its soluble decoy receptor, osteoprotegerin (OPG), are critical regulators of bone remodeling. Binding of RANKL to its cognate receptor RANK, expressed on osteoclasts and its precursors, induces NF- B signaling, resulting in NF- B translocation to the nucleus with a subsequentincrease in RelB levels, in turn, stimulating osteoclastic differentiation  (Figure, A). OPG, a decoy receptor, expressed by osteoblasts, binds with RANKL, preventing RANK (receptor activator of NF- B) signaling and thus inhibiting osteoclastogenesis (Figure, B).7

                 Vascular calcification is a pathological sequence of events that has similarities to the normal physiological process of osteogenesis. It is thought to result from an imbalance in both local and systemic inhibitors and promoters, which occurs as a consequence of chronic inflammation, hyperleptinemia, and a deregulation of various bone-regulating proteins. It is common in patients with diabetes and renal failure and in the elderly. 

Vascular calcification significantly impairs cardiovascular physiology, and its mechanism is under investigation. Many of the same factors that modulate bone osteogenesis, including cytokines, hormones, and lipids, also modulate vascular calcification, acting through many of the same transcription factors. In some cases, such as for lipids and cytokines, the net effect on calcification is positive in the artery wall and negative in bone.

Arterial calcification and bone mineralization

• A recent series of reports points to the possibility that two bone regulatory factors, receptor activator of NF-kappaB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG), govern vascular calcification and may explain the phenomenon.

• Both RANKL and OPG are widely accepted as the final common pathway for most factors and processes affecting bone resorption. Binding of RANKL to its cognate receptor RANK induces NF-kappaB signaling, which stimulates osteoclastic differentiation in preosteoclasts and induces bone morphogenetic protein (BMP-2) expression in chondrocytes.

Arterial calcification and bone mineralization

A role for RANKL and its receptors in vascular calcification is supported by several findings:--• a vascular calcification phenotype in mice

genetically deficient in OPG; • an increase in expression of RANKL, • a decrease in expression of OPG, in calcified

arteries; • clinical associations between coronary disease

and serum OPG and RANKL levels; • RANKL induction of calcification and osteoblastic

differentiation in valvular myofibroblasts.

Arterial calcification and bone mineralization

RANK Ligand and Osteoprotegerin. Paracrine Regulators of Bone Metabolism and Vascular

Function– Receptor activator of nuclear factor (NF-kappaB)

ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system.

– RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss.

– RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways..

RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.

RANK Ligand and Osteoprotegerin

• A recent series of reports points to the possibility that two bone regulatory factors, receptor activator of NF-kappaB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG), govern vascular calcification and may explain the phenomenon.

• Both RANKL and OPG are widely accepted as the final common pathway for most factors and processes affecting bone resorption. Binding of RANKL to its cognate receptor RANK induces NF-kappaB signaling, which stimulates osteoclastic differentiation in preosteoclasts and induces bone morphogenetic protein (BMP-2) expression in chondrocytes.

RANK Ligand and Osteoprotegerin

The molecular triad OPG/RANK/RANKL

The recent identification of the receptor activator of nuclear factor kappaB ligand (RANKL), its cognate receptor RANK, and its decoy receptor osteoprotegerin (OPG) has led to a new molecular perspective on osteoclast biology and bone homeostasis. Specifically, the interaction between RANKL and RANK has been shown to be required for osteoclast differentiation.

The third protagonist, OPG, acts as a soluble receptor antagonist for RANKL that prevents it from binding to and activating RANK. Any dysregulation of their respective expression leads to pathological conditions such as bone tumor-associated osteolysis, immune disease, or cardiovascular pathology. In this context, the OPG/RANK/RANKL triad opens novel therapeutic areas in diseases characterized by excessive bone resorption.

Oncogenesis + bone modulators Effective therapies for both primary and secondary bone tumors are actually

required. Bone homeostasis depends on the strictly balanced activities between bone formation by osteoblasts and bone resorption by osteoclasts. Imbalance of bone formation and resorption results in various bone diseases. Both primary and secondary bone tumors develop in the unique environment bone, it is therefore necessary to understand bone cell biology in tumoral bone environment.

Recent findings strongly revealed the significant involvement of the receptor activator of nuclear factor RANKL/RANK/OPG triad, the key regulators of bone remodeling in bone oncology. Indeed, RANKL/RANK blocking successfully prevented the development of bone metastases. Furthermore, some cancer cells express RANK which is involved in tumor cell migration. Thus, the regulation of this triad will be a rational, encouraged therapeutic hot spot in bone oncology. In this review, we summarize the accumulating knowledge of the RANKL/RANK/OPG triad and discuss about its therapeutic capability in primary and secondary bone tumors.

Key roles of the OPG-RANK-RANKL in bone oncology.

Osteoprotegerin (OPG)-receptor activator of nuclear factor-kappaB (RANK) and RANK ligand (RANKL) have been identified as members of a ligand-receptor system that directly regulates osteoclast differentiation and osteolysis. RANKL may be a powerful inducer of bone resorption through its interaction with RANK, and OPG is a soluble decoy receptor that acts as a strong inhibitor of osteoclastic differentiation. Any dysregulation of their respective expression leads to pathological conditions. Furthermore, recent data demonstrate that the OPG-RANK-RANKL system modulates cancer cell migration, thus controlling the development of bone metastases. This review describes the most recent knowledge on the OPG-RANK-RANKL system, its involvement in bone oncology and the new therapeutic approaches based on this molecular triad.

Osteolytic and osteoblastic metastases are often the cause of considerable morbidity in patients with advanced prostate and breast carcinoma. Breast carcinoma metastasis to bone occurs because bone provides a favorable site for aggressive behavior of metastatic cancer cells. A vicious cycle arises between cancer cells and the bone microenvironment, which is mediated by the production of growth factors such as transforming growth factor beta and insulin growth factor from bone and parathyroid hormone-related protein (PTHrP) produced by tumor cells.

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bone oncology

Osteolysis and tumor cell accumulation can be interrupted by inhibiting any of these limbs of the vicious cycle. For example, bisphosphonates inhibit both bone lesions and tumor cell burden in bone in experimental models of breast carcinomametastasis. Neutralizing antibodies to PTHrP, which inhibit PTHrP effects on osteoclastic bone resorption, also reduce osteolytic bone lesions and tumor burden in bone.

Other pharmacologic approaches to inhibit PTHrP produced

by breast carcinoma cells in the bone microenvironment also produce similar beneficial effects. Identification of the molecular mechanisms responsible for osteolytic metastases is crucial in designing effective therapy for this devastating complication

bone oncology

Ca Prostrate• Prostate cancer cells produce a variety of pro-

osteoblastic factors that promote bone mineralization. For example, both bone morphogenetic proteins and endothelin-1 have well recognized pro-osteoblastic activities and are produced by prostate cancer cells. In addition to factors that enhance bone mineralization prostate cancer cells produced factors that promote osteoclast activity. Perhaps the most critical pro-osteoclastogenic factor produced by prostate cancer cells is receptor activator of RANKL, which has been shown to be required for the development of osteoclasts.

Ca Prostrate

• Blocking RANKL results in inhibiting prostate cancer-induced osteoclastogenesis and inhibits development and progression of prostate tumor growth in bone. These findings suggest that targeting osteoclast activity may be of therapeutic benefit. However, it remains to be defined how prostate cancer cells synchronize the combination of osteoclastic and osteoblastic activity.

• Vascular endothelial growth factor (VEGF) has been shown recently to promote osteoblast activity.

• Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism, and promote the ability of the prostate cancer cells to invade the bone microenvironment.

Ca Prostrate• Within the past few years, several studies showed that

increased osteolytic activity also occurs in the background of the prostate cancer skeletal metastases. Because growth factors are being released from the bone matrix during degradation, it suggests that inhibition of osteolysis might be effective in slowing tumor growth. Several strategies are being developed and applied to affect directly the osteolytic events, including use of bisphosphonates and targeting the critical biological regulators of osteoclastogenesis, receptor activator of nuclear factor- B and receptor activator of nuclear factor- B ligand.

parathyroid hormone-related peptide (PTH-rP) hypercalcemia

• Solid cancers metastasize to bone by a multi-step process that involves interactions between tumor cells and normal host cells. Some tumors, most notably breast and prostate carcinomas, grow avidly in bone because the bone microenvironment provides a favorable soil. In the case of breast carcinoma, the final step in bone metastasis (namely bone destruction) is mediated by osteoclasts that are stimulated by local production of the tumor peptide parathyroid hormone-related peptide (PTH-rP), whereas prostate carcinomas stimulate osteoblasts to make new bone. Production of PTH-rP by breast carcinoma cells in bone is enhanced by growth factors produced as a consequence of normal bone remodeling, particularly activated transforming growth factor-beta (TGF-beta). Thus, a vicious cycle exists in bone between production by the tumor cells of mediators such as PTH-rP and subsequent production by bone of growth factors such as TGF-beta, which enhance PTH-rP production.

Bone Metastasis

parathyroid hormone-related peptide (PTH-rP) hypercalcemia

• The metastatic process can be interrupted either by neutralization of PTH-rP or by rendering the tumor cells unresponsive to TGF-beta, both of which can be accomplished experimentally. The osteoclast is another available site for therapeutic intervention in the bone metastatic process. Osteoclasts can be inhibited by drugs such as the new-generation bisphosphonates; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia. However and possibly even more importantly, there is also a reduction of tumor burden in bone.

• The precise mechanism by which bisphosphonates inhibit osteoclasts is still unclear and may represent a combination of inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. However, studies with potent bisphosphonates have clearly documented that reduction of bone turnover and osteoclast activity leads to beneficial effects not only on skeletal complications associated with metastatic cancer, but also on tumor burden in bone.

Bone Metastasis

Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastasis to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to non bone sites.

These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth.

parathyroid hormone-related peptide (PTH-rP) hypercalcemia

Bone Metastasis

Recent findings of the Receptor Activator of Nuclear Factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) molecular triad, the key regulators of bone remodeling, opened new era of bone research.

Although RANK is an essential receptor for osteoclast formation, activation and survival, functional RANK expression has been recently identified on several bone-associated tumor cells.

When RANK is expressed on secondary bone tumor cells, it is implicated in tumor cell migration, whereas this is not the case for primary bone tumors. In any case, RANK is not involved in RANK-positive cell proliferation or death.

Experimental data revealed that local differentiation factors, such as RANKL, play an important role in cell migration in a metastatic tissue-specific manner. These findings substantiate the novel direct role of RANKL/RANK in bone-associated tumors, and its capability of representing new therapeutic targets.

Bone Metastasis

The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector.

Data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone.

parathyroid hormone-related peptide (PTH-rP) hypercalcaemia

Bone Metastasis

Breast carcinoma commonly metastasizes to the skeleton in patients with advanced disease, hypercalcemia, fracture, and nerve-compression syndromes. The bone destruction is mediated by the osteoclast. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process. Transforming growth factor beta (TGFbeta), which is abundant in bone matrix and is released as a consequence of osteoclastic bone resorption, may promote breast carcinoma osteolysis by stimulating PTHrP production by tumor cells. These data indicate a central role for TGFbeta in the pathogenesis of osteolytic bone metastases from breast carcinoma by 1) the induction of PTHrP through the Smad signaling pathway and 2) the potentiation of ER-alpha-mediated transcription induced by a constitutively active ER-alpha. Understanding the mechanisms of osteolysis at a molecular level will generate more effective therapeutic agents for patients with this devastating complication of cancer.

parathyroid hormone-related peptide (PTH-rP) hypercalcemia

Bone Metastasis

Thyroid and MBD• There is an increasing prevalence of high levels of thyroid stimulating

hormone (TSH) with age - particularly in postmenopausal women - which are higher than in men.

• The incidence of thyroid disease in a population of postmenopausal women is as follows: clinical thyroid disease, about 2.4%; sub clinical thyroid disease, about 23.2%.

• Among the group with sub clinical thyroid disease, 73.8% are hypothyroid and 26.2% are hyperthyroid.

• The rate of thyroid cancer increases with age. • The symptoms of thyroid disease can be similar to postmenopausal

complaints and are clinically difficult to differentiate. There can also be an absence of clinical symptoms. It is of importance that even mild thyroid failure can have a number of clinical effects such as depression, memory loss, cognitive impairment and a variety of neuromuscular complaints. Myocardial function has been found to be subtly impaired.

• There is also an increased cardiovascular risk, caused by increased serum total cholesterol and low-density lipoprotein cholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxin replacement therapy.

Recommendations• Patients taking thyroid hormone for treatment of hypothyroidism should

maintain their TSH in the normal but not suppressed range.

• Patients taking thyroid hormone to suppress further growth of thyroid nodules should maintain their TSH in the low normal range

• Patients taking thyroid hormone for the treatment of thyroid cancer should maintain their TSH in the suppressed range, using the minimal dose of thyroxin required to achieve TSH suppression

• If osteoporosis is a concern, attention should be paid to risk factors, exercise, diet, calcium and vitamin D supplementation, and if necessary, additional medications for the treatment of osteoporosis can be considered. 

• Patients with thyroid cancer who face lifelong excess thyroid hormone replacement should consider a baseline bone density to establish parameters for sequential monitoring of bone density over time.

Summary

• Obesity has high Bone mineral mass.

• Hypothyroidism is associated more with body mass index which in turn increase bone mineral density.

• Post menopause state is more associated with peripheral arterial calcification.

• Aortic calcification is more common in Post Menopause state.

Summary

• The incidence of coronary artery disease is four times less in post menopause female than in male.

• The distribution of body fat is directly under the control of Hypothalamus.

• Females are more prone for Osteoarthritis and male for Coronary diseases.

Summary

• Treatment of certain diseases in post menopausal state itself may be the cause of osteoporosis.

• Type 2DM treatment with oral hypoglycemic agents increases chances of fracture.

• Treatment of increased TSH (Hypothyroidism) by l-thyroxin may cause osteoporosis.

Summary

• Hypercalcemia in metastatic bone diseases is due to PTHrP type hormones secreted by tumor cells.

• The mechanism of new bone formation is same as bone formation in the normal bone remodeling process.

• Bone destruction in Multiple Myeloma is primarily due to space occupying lesion in the bone marrow space.

Summary & Conclusion

• Blocked of transcription factors like RANK, RANK-L, Osteoprotegerin are the future tools with the scientists for treatment of arterial & coronary calcification, hypercalcemia, metastatic bone diseases especially of prostrate and breasts, or any PTHrP secreting tumors.

• leptin might eventually be used to prevent the loss of bone in astronauts during long voyages in space.

• Information contained and transmitted by this presentation is based on personal experience and collection of cases at Choithram Hospital & Research centre, Indore, India, during past 30 years.• It is intended for use only by the students of orthopaedic surgery. •Many GIF files are taken from Internet.• Views and opinion expressed in this presentation are personal opinion.• Depending upon the x-rays and clinical presentations viewers can make their own opinion.• For any confusion please contact the sole author for clarification.• Every body is allowed to copy or download and use the material best suited to him. I am not responsible for any controversies arise out of this presentation.• For any correction or suggestion please contact naneria@yahoo.com

DISCLAIMER

Bon Voyage