BoneKEy-Osteovision | Meeting Reports
Meeting report from the 1st joint meeting of the international bone and mineral society and the Japanese society for bone and mineral research
DOI:10.1138/20030110
Osteoporosis: Assessment and treatment Richard L. Prince, Department of Medicine, Sir Charles Gairdner Hospital, Perth, Western AustraliaSixteen excellent presentations were given in this session. The majority of the presentations took five minutes, which was at times a little stressful, at least for the Chairs. As expected, the data covered were extremely broad.
In vitro structure analysisAn interesting study () of 26 early postmenopausal women showed that there was no increase in trabecular separation or star volume, a measure of the space between the trabeculae, in those treated with risedronate, whereas significant deterioration was seen in the placebo-treated group. The authors suggest that the early effect to stop deterioration in trabecular structure could account for the early fracture reduction effects noted in the multicenter risedronate studies.
Investigators associated with Novartis reported an interesting effect of intravenous zoledronic acid in ovariectomized rats (). Quantitative computed tomography (QCT) showed a 26% reduction in cortex and a 55% reduction in cancellous bone mineral density (BMD) in the proximal metaphysis of the tibia. Full protection against bone loss was achieved with a single dose of zoledronic acid (20 mg/kg), given 32 weeks before the measurement. Higher doses improved the mechanical strength of the femur and lumbar vertebral bodies. The authors concluded that these animal data support human data showing a significant effect of a single dose of zoledronic acid on bone density and further suggest that bone strength is also improved.
Strontium, another interesting new therapeutic compound, was also studied in ovariectomized rats by investigators associated with Servier (). The rats showed an increase in trabecular bone volume (36% to 115%) and in bone and mineral strength (26%). Bone mineralization seemed to be normal, but the high bone turnover expected after ovariectomy was unaltered. Thus, strontium seems to have strong effects on the balance between bone formation and resorption, in that bone mass is substantially increased in this rat model.
Fracture endpoint studiesIn a posthoc analysis of the hip intervention program in 9331 elderly women (), risedronate had a protective effect on preventing both femoral neck and intertrochanteric fractures in osteoporotic women.
A second randomized, controlled trial of hip protectors, with hip fracture as the outcome, was described (). The Sydney investigators reported two studies — one study of 134 women in residential care and another study of 600 community-dwelling individuals, neither of which showed significant treatment benefit. Unfortunately, the use of hip protectors was approximately 50% in both studies. In the community study, hip protectors reduced the risk of fracture, if worn during a falling episode. The investigators indicated that further development of hip protectors will have to take into account patient preference for use.
Bone mineral density studiesSix papers used BMD to assess the effects of interventions involving physical, nutritional, hormonal, or chemical measures.
An interesting and somewhat heterogeneous group of pre- and postpubertal children with disabling conditions were randomized to an effect of low magnitude, high frequency mechanical stimulation provided by a vibrating plate on which the patient stood (). The data showed a beneficial effect on QCT measurements at the proximal tibia, but no effect on spinal bone density. These data support the long-held belief that mechanical stimulation of bone promotes improved architecture, in this case a 20% improvement in trabecular bone density.
A randomized, controlled trial of milk supplementation in 173 postmenopausal Malaysian women showed that high-calcium (1200 mg) skim milk significantly reduced bone loss at the total body, lumbar spine, and femoral neck, compared with control patients (). These data support the effectiveness of calcium supplementation previously reported in postmenopausal white women.
A small randomized, controlled trial of growth hormone therapy in 10 patients who had required surgery for hip fracture showed that approximately one month of treatment reduced loss of weight, lean body mass, and total body bone mineral content three months after surgery (). These data raise the interesting possibility of the use of growth hormone therapy after surgery.
A three-arm randomized, controlled trial of calcitriol, ergocalciferol, and alendronate showed that after two years of therapy, alendronate had a statistically significantly larger improvement in lumbar spine BMD than did calcitriol or ergocalciferol (). No overall difference was found between the three groups at the femoral neck site. There was no difference in results between the two vitamin D groups. These data suggest that alendronate is superior to both vitamin D2 and calcitriol in males or females starting therapy and in those already receiving glucocorticoid therapy.
An ovariectomized monkey study of teriparatide showed that 18 months of therapy increased vertebral yield force by 41% in ovariectomized controls (). In vivo dual-energy x-ray absorptiometry measurement showed that both bone mineral content (BMC) and projected area increased relative to baseline (21% and 5%, respectively) in animals treated with teriparatide. The authors commented that the 21% increase in BMC underestimated improvement in bone strength.
Finally, a study of intravenous ibandronate in 627 nonosteoporotic postmenopausal women showed a dose-dependent increase in lumbar spine and femoral neck BMD after one year of therapy (). Ibandronate was given every 3 months. These data support the belief that intermittent intravenous therapy will become an approved approach to prevention of osteoporotic fracture.
New noninvasive methods of assessing bone strengthTwo papers examined modern approaches to noninvasive evaluation of bone structure and strength, one utilizing magnetic resonance imaging (MRI) (), the other utilizing CT (). The MRI study of ex vivo femoral and spine bone samples suggested that some aspects of MRI output may correlate reasonably well with bone strength. Substantial work clearly needs to be done to improve BMD prediction.
A second paper studied the potential of CT-based finite element modeling of the contralateral femur in 15 patients with hip fracture and in 5 normal patients (). A mathematical model to access stance- and fall-loading conditions showed substantial reduction in bone strength in the patients with hip fracture. These preliminary data may form the basis of a method for improving fracture predictions, especially at the hip site.
EpidemiologyFinally, a paper from Sweden examined the epidemiology of cervical and intertrochanteric hip fractures (). The authors identified a variety of risk factors that may suggest a differential risk for trochanter versus cervical fractures.
Bone formation, cartilage, and bone matrix Roberto Civitelli, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA The cartilage between bone modeling and articular degenerationAchondroplasia is the most common genetic form of dwarfism, and it is caused by mutations of fibroblast growth factor receptors (FGFRs). Using a mouse model of achondroplasia with targeted overexpression of activated FGFR3 in chondrocytes, investigators found that C-type natriuretic peptide (CNP) rescued the dwarfism phenotype () by increasing extracellular matrix production, with little alteration in proliferation or differentiation of growth plate chondrocytes. Thus, CNP may offer some hope for the treatment of this otherwise untreatable condition. The relationship between chondrocyte proliferation and differentiation was analyzed in the spontaneously occurring dwarf miniature rat Ishikawa (MRI) model (). The gene responsible for this phenotype (MRI) was identified as a cyclic guanosine monophosphate (cGMP)-dependent protein kinase 2, whose kinase domain is deleted in MRI rats. This defect “uncouples” chondrocyte proliferation and differentiation, resulting in a larger growth plate (in a smaller bone) with flattened chondrocytes and reduced extracellular matrix. In another study (), marked expression of osteopontin was demonstrated not only in hypertrophic chondrocytes, but also in proliferative and resting chondrocytes, in one in vivo study of transgenic mice expressing a fluorescent reporter gene (green fluorescent protein) under the control of different fragments of the osteopontin promoter. Thus, osteopontin, which is involved in physiological and pathological calcification, may also participate in regulation of chondrocyte proliferation and differentiation in the growth plate.
An intriguing study suggested potential benefits of alendronate, a potent bisphosphonate, in osteoarthritis (). Investigators evaluated the effect of alendronate on cartilage degradation and periarticular bone changes in the rat anterior cruciate ligament transection model of osteoarthritis. Alendronate inhibited ligament transection-induced subchondral bone remodeling, improved histologic scores of cartilage damage, and inhibited osteophyte formation. These provocative results demonstrate that subchondral bone remodeling is critically important for osteoarthritis progression and raise the possibility that bone resorption inhibitors may be used to slow the progression of osteoarthritis.
The Proteasome System As a Modulator of Osteoanabolism Via Bone Morphogenetic Protein Signaling
Bone morphogenetic protein (BMP) signaling participates in the mechanism of action of anabolic factors, including proteasome inhibitors, which have recently been shown to stimulate new bone formation (). Through elegant molecular biology studies, the same group of investigators () reported that this action is mediated by inhibition of proteolytic processing of Gli3, a repressor of BMP-2 gene transcription, which acts on specific regulatory elements in the BMP-2 promoter. Thus, release from an inhibitory brake results in increased BMP-2 expression and stimulation of bone formation by proteasome inhibitors. The therapeutic potential of these agents is currently being tested in animal studies. The importance of the ubiquitin-proteasome system for BMP signaling is also underscored by a study demonstrating that BMP receptors can be targeted by inhibitory Smads-Smurf1 complexes for ubiquitination and proteolytic degradation (). In this scenario, Smurf1 synergizes with Smad6 to inhibit BMP signaling. Upregulation of Smad3, another effector of the BMP signaling system, may be linked to the anabolic action of parathyroid hormone (PTH) (). Overexpression of Smad3 can reproduce the antiapoptotic effect of PTH in osteoblastic cell lines and enhance the stimulatory action of transforming growth factor-b on osteoblast function, thus contributing to new bone formation.
Angiogenesis: The foundation of bone regenerationAngiogenesis plays an important role during bone development and fracture healing, and Id1 and Id3 are required for angiogenesis in tumors. Although single gene deletion of Id1 or Id3 has no major consequences, deletion of Id3 in an Id1 heterologous background (Id1+/-Id3-/-) impairs angiogenesis in the callus during fracture repair, despite a normal number of chondrocytes (). This leads to delayed callus remodeling and reduced new bone formation. Furthermore, ectopic bone formation induced by BMP-2 injection in calvaria is also dramatically reduced in Id1+/-Id3-/- double mutant mice, implying that angiogenesis and Id1 and Id3 function are required for fracture healing and BMP-2 anabolic action.
Intercellular communication and peak bone mass acquisitionCell-cell communication via gap junctions allows diffusion of locally generated signals among bone cells, and in particular, from osteocytes to osteoblasts on the bone surface. Using the Cre/loxP approach, one group has achieved osteoblast-specific inactivation of the gene for connexin43, the major gap junction protein in bone cells (). Total body bone density measured by dual-energy x-ray absorptiometry was lower in osteoblast connexin43-deleted animals, an osteopenic phenotype that was more pronounced in females than in males and when the gene was deleted at early stages of osteoblast differentiation. In vitro studies also demonstrated reduced matrix production and mineralization by connexin43-deficient osteoblasts. Thus, connexin43 gap junctional communication is critically important for adult bone homeostasis, contributing to the achievement of peak bone mass. Mechanically generated signals can be propagated by cell-cell communication and can induce gene transcription. One study reported induction of FosB/DfosB gene transcription by application of fluid shear stress to osteoblasts (). This effect is indirect, via calcium-dependent activation of extracellular signal-regulated kinase (ERK) phosphorylation, which in turn, modulates the activity of a transcriptional complex binding to a shear stress response element.
Making new bone-forming cells via transcriptional regulationThe number of transcriptionally active factors that controls the differentiation and function of chondrocytes and osteoblasts is increasing. Using an elegant gene-trapping approach applied to murine chondrogenic precursor cells, one group of investigators () identified nuclear factor IB (NFIB), a member of the nuclear factor I family of DNA-binding proteins, as a new candidate regulator of chondrogenesis. Similarly, Msx2, a member of the homeobox gene family and critical in craniofacial development, is also a stimulator of osteoblastogenesis (). Overexpression of Msx2 promotes osteoblastic differentiation from the multipotent, uncommitted C3H10T1/2 and C2C12 cell lines — an effect enhanced by BMP-2 — and augments matrix mineralization in calvaria cells. Of interest, this action is independent of Cbfa1/Runx2, one of the master genes thought to be required for bone formation. Thus, Msx2 promotes both early and late stages of osteoblastic differentiation. Because osteoblastogenesis and adipogenesis are alternative differentiation pathways of mesenchymal stem cells, it would be interesting to see if Msx2 also inhibits adipogenesis. In this regard, inhibition of BMP signaling by overexpression of noggin in calvaria cells induces adipogenic differentiation and upregulation of adipogenic markers (PPARg and adipsin2) in calvaria cells, while inhibiting osteoblast differentiation (). These results further strengthen the role of BMPs in mesenchymal cell fate.
Absolute fracture risk as an indication for therapy in osteoporosis Olof Johnell, Department of Orthopaedics, University Hospital Malmö, Malmö, SwedenThe morning of June 6, 2003 was devoted to risk assessment. Professor Dennis Black provided background information about the incidence and calculation of absolute risk, as well as data from the Far East and principal risk factors from the Study of Osteoporotic Fractures.
Professor Olof Johnell discussed how risk assessment should be performed.
Most pharmaceutical studies have been performed using dual-energy x-ray absorptiometry (DXA). At present, bone mineral density (BMD) T score is the primary indication for intervention. There are several advantages: T score is an inclusion criterion, T score is established among osteoporosis doctors, and a high T score has a high relative risk in younger patients. There are some disadvantages: T score is only defined for DXA, absolute risk is different at different ages for the same T score (see below), T score is different for different techniques, many high-risk individuals go undetected by only using T score, and DXA is not available everywhere. These considerations led us to the view that intervention thresholds should be based on absolute risk (i.e., probability of fracture). The use of absolute risk has the potential of being applicable to both sexes, all ages, and all races. Similar approaches are now used in the management of cardiovascular disease; a 10-year time frame accommodates treatment for five years, with onset of effect over the subsequent five years. At present, the problem is discussed with the use of T score because the 10-year absolute risk for a given T score is age dependent. For example, a woman with a T score of –2.5 at age 60 years has an absolute risk for hip fracture of 4.4%, whereas at age 80 years, the absolute risk is 11.3%. The figures for any hip, wrist, spine, or shoulder fracture are 16.2% and 25.6% at ages 60 and 80 years, respectively.
It is also important to include other fractures in the 10-year risk assessment. How should a 10-year risk assessment be performed? This could be done by merging a well-validated international dataset. As a risk factor, BMD is a cornerstone, but other risk factors must be included. For fracture prediction, the chosen risk factor should be validated in multiple populations and be adjusted for age, sex, and type of fracture. It should also be readily assessable by primary care physicians, contribute to a risk that is amenable to the therapeutic manipulation intended, and be intuitive to medical care. It is also important to study how risk factors differ by sex, age, or value. Examples of strong risk factors are age, sex, low BMD, low energy trauma, fracture after age 50 years, and glucocorticoid treatment. Other important risk factors are low body mass index, smoking, heredity, secondary osteoporosis, and so forth. The cutoff for 10-year risk for pharmaceutical intervention should be partly based on cost effectiveness. Then the intervention threshold can be divided into three parts, with three choices possible: no further assessment or treatment required because of low absolute fracture risk; further assessment indicated, such as diagnostic assessment with DXA; and treatment indicated irrespective of any diagnostic assessment when the risk is very high. This concept has already been accepted in the cardiovascular field, and the indication is partly based on 10-year risk.
Osteoporosis: Pathophysiology, genetics, and epidemiologyGenetic influence is a hot topic. In the previous session, the low-density lipoprotein receptor-related protein 5 (LRP5) gene was discussed, and new exciting data were also presented on the influence of genetics on other diseases.
This session started with a discussion of genetics. The first presentation was on the Dubbo Osteoporosis Epidemiology study, a study in which researchers examined the genetic influence in families and the heredity of bone mineral density (BMD) in males and females (). The findings support the hypothesis that a large component of the variance of BMD is under genetic control, and this analysis provides evidence of a major gene locus influencing BMD within family groups.
Another presentation focused on whether chromosome X affects bone loss in mice (). The study group identified quantitative trait loci on chromosomes 11, 13, and X.
In another presentation on the Dubbo study, the gene polymorphisms of vitamin D receptor (VDR) and collagen type I alpha 1 (COLIA 1) genotypes were examined for risk of hip fracture (). It was concluded that in white women, the VDR tt and COLIA 1 ss genotypes independently contributed to the risk of hip fracture, even after adjustment for age and BMD.
In a study conducted in Hong Kong, risk factors and polymorphisms of estrogen receptors (ERs) alpha and beta were studied. Of interest, body weight, together with ER beta gene polymorphism, explained 80% of the variance of bone mass in premenopausal women, whereas age, weight, and environmental factors explained 47% of the variance of bone mass in postmenopausal women ().
Risk factors for osteoporosis were also discussed in this session. In a study carried out in Australia, increased levels of serum parathyroid hormone (PTH) were significantly associated with mortality, independent of age and sex, and serum 25 OHD was associated with static balance and serum PTH levels in fallers, but not in nonfallers (). Thus, serum PTH may be an important factor for determining fall risk.
In another presentation, the authors concluded that drinking green tea is associated with increased BMD in elderly women, and suggested that the association could possibly be mediated by flavonoids ().
In summary, the discussion of genetics in this session is was important because of the debate surrounding which polymorphism is the most important. The first presentation showed that there might be a major gene locus influencing BMD. It is also interesting that polymorphisms from VDR and COLIA 1 genotypes are independently important for hip fracture. With regard to risk factors, a discussion highlighted the importance of PTH in determining risk of falls.
Systemic and local regulation of skeleton metabolism Henry M. Kronenberg, Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USAIn this session, a number of novel regulators of osteoblasts were analyzed. In this brief summary, studies of the actions of the vitamin D receptor, lactoferrin, and hypothalamic signaling are summarized.
OR63 and OR66These presentations addressed possible direct roles for vitamin D in the regulation of bone formation. Although cells of the osteoblast lineage express vitamin D receptors (VDRs), and administration of 1,25(OH)2D3 to isolated osteoblasts regulates gene expression, the role of VDR in bone cells in vivo remains obscure. The obvious morphologic abnormalities of the bones of VDR knockout mice can be prevented with a diet high in calcium, phosphorus, and lactose. Thus, these abnormalities in bone are indirect consequences of mineral metabolism. The dramatic indirect effects of activation of VDR, however, might well obscure direct effects that are meaningful. To elicit such effects in an in vivo model, Tanaka et al. () and Inoue et al. () transplanted femurs and calvariae from wild-type (WT) or VDR knockout mice at two weeks of age, a time before obvious rickets occurs, into the subcutaneous tissue of WT mice. Four weeks after transplantation, bone density, cortical thickness, and bone formation rates were all increased in the bones of the VDR knockout mice. To determine whether the changes could occur without the participation of host cells, the investigators performed the experiments also after wrapping the bones in a cell-impermeable membrane. Again, the VDR knockout mice exhibited increased bone formation, compared with WT mice, although the effect was more modest than in the absence of the membrane. Because the transplanted VDR knockout bone had higher runx2 mRNA levels, the investigators suggested that a normal function of VDR is to suppress runx2 levels in osteoblasts. These studies were reinforced by careful analyses of newborn VDR knockout mice, which exhibited increased diaphyseal cortical bone, and by organ culture studies, in which VDR knockout femurs exhibited substantial increases in cortical thickness, compared with WT femurs. These experiments suggest that VDR may contribute direct actions to osteoblast biology in vivo, at least in some circumstances.
OR64Lactoferrin is a milk protein that circulates. These investigators identified lactoferrin as an osteoblast growth factor in milk (). Lactoferrin causes osteoblastic cell proliferation in vitro and decreases osteoclastogenesis in marrow cultures. Protein increases bone formation when injected adjacent to murine calvariae in vivo. The investigators showed that receptor-associated protein (RAP), an inhibitor of low-density lipoprotein (LDL) receptor-like proteins, LRP1 and LRP2, inhibits endocytosis of lactoferrin in primary osteoblastic cells. They also showed that lactoferrin activates the mitogen-activated protein kinase (MAPK) pathway in osteoblastic cells. Stimulation of osteoblastic cell proliferation was also blocked by RAP and MAPK kinase inhibitors. The action of lactoferrin was greatly diminished in LRP1 null fibroblasts. Thus, lactoferrin is thought to stimulate osteoblastic cell proliferation following interaction with (and internalization by) LRP1 and activation of the MAPK pathway. The relevance of these observations to the in vivo situation now needs to be established, both in mothers and in milk-fed neonates.
OR65 and OR75The previous work of Karsenty's group has shown that leptin acts on neurons that are sensitive to goldthioglucose to decrease bone mass. In addition, the group previously had shown that monosodium glutamate administration did not alter bone mass. This was a surprising result because monosodium glutamate administration causes hypogonadism. Here the investigators found that monosodium glutamate does, in fact, cause an increase in bone resorption, but that it also causes an increase in bone formation (). When hypogonadism is corrected by physiologic estrogen administration, monosodium glutamate administration leads to a clear increase in bone mass. Thus, a central mechanism, independent of leptin, is also a regulator of bone mass.
In Abstract 75, the authors addressed the relevance of leptin's action in human bones. They showed that a patient with lipodystrophy has a high bone mass. They further studied a murine model of lipodystrophy, in which all white adipose tissue was ablated (). In these mice, with leptin levels diminished 20-fold from normal, bone mass was increased. This increase was not found in lipodystrophic mice overexpressing leptin through a transgene. Thus, these studies further show that leptin, independent of fat mass, decreases bone mass. In addition, the studies suggest that the findings are applicable to humans and demonstrate that leptin-independent mechanisms control bone mass centrally.
Clinical conditions other than osteoporosis Jean-Jacques Body, Institut J. Bordet, Department of Medicine, Université Libre de Bruxelles, Brussels, BelgiumMost of the abstracts in this session were related to the pathogenesis of tumor-induced osteolysis. Further developments on the reciprocal relationship between cancer cells and bone (cf. “seed and soil theory”) were presented, reemphasizing the vicious cycle that is so characteristic of malignant osteolysis ().
Breast cancerIt has been hypothesized that the osteotropism of breast cancer cells can be partly explained by their expression of bone proteins, such as bone sialoprotein (BSP) or osteonectin (). In line with this theory, it was reported that overexpression of BSP by MDA-MB-231 cells increases the extent of bone metastases in the classical model of intraventricular injection of MDA cells in nude mice (). Osteopontin seems to be an autocrine growth-promoting factor favoring the development of bone metastases. An antisense osteopontin construction reduces the tumorigenicity of breast cancer cells and the subsequent development of bone metastases. Similarly, neutralizing antibodies against osteopontin inhibit the proliferation of osteopontin-producing breast cancer cells. In agreement with the “seed and soil theory,” the production of osteopontin by 4T1 cells is stimulated by transforming growth factor-b (). The same growth factor was also shown to increase prostaglandin production by breast cancer cells, which could contribute to their osteolytic potential ().
The expression of cadherin-11 was reported to be increased in bone-seeking clones of MDA cells and seems to favor the early stages of bone colonization by cancer cells (). The dialogue between cancer and bone cells was again confirmed as a co-culture between osteoblasts and cancer cells increased parathyroid hormone-related protein production in cadherin-11 overexpressing cells, leading to enhanced osteoclast formation via cadherin-11–mediated interactions with stromal/osteoblastic cells. If a lot of emphasis has been placed on the effects of bone-derived bone growth factors on cancer cells, much less attention has been paid to the potential effects of enhanced bone mineral release. Preliminary data were presented suggesting that calcium released during the process of tumor-induced osteolysis could be of some pathogenic importance. Calcium indeed seems to exert weak "estrogen-like effects" on estrogen receptor (ER) - positive breast cancer cells, inducing progesterone receptor expression and stimulating ER transcriptional activity (). This action is mediated through the membrane calcium receptor. This work proceeds along the same lines of recently published findings ().
MyelomaThe “vicious cycle” between cancer and bone cells is also well established in myeloma bone disease and was confirmed during this meeting. Osteoclasts can stimulate myeloma cell growth and can rescue them from apoptosis. This activity is contact dependent, but, of interest, largely interleukin-6 independent and apparently osteopontin dependent (). Conversely, myeloma cells can secrete factors that suppress osteoblast differentiation, probably through blockade of bone morphogenetic protein-2 signaling pathways, which could contribute to the typical uncoupling observed in myeloma bone disease ().
Cancer, miscellaneousThe effects of chemotherapy on bone cells have been little investigated. It was shown that docetaxel, a taxane increasingly used in the clinic, inhibits osteoclast differentiation in vitro (). Bisphosphonates are known to exert various “antineoplastic” effects on tumor cells, although the clinical relevance of these effects remains unproven (). The effects of zoledronic acid on PC-3 prostate cancer cells seem to be particularly impressive, exerting both cytostatic and apoptotic effects (). Because such “antineoplastic” effects pass through an inhibition of the mevalonate pathway, it was not surprising to find that the degree of Ras activation in mesenchymal tumors correlates with the antiproliferative activity of the bisphosphonate incadronate (). Other inhibitors of osteoclast-mediated bone resorption are in development, and it was reported that a new nonpeptide bone-targeted src tyrosine kinase inhibitor can prevent the development of bone metastases in nude mice following intracardiac injection of MDA cells ().
Diseases other than cancerHypophosphatasia is characterized by elevated pyrophosphate levels, which is a potent inhibitor of bone mineralization. Mice made deficient in inorganic pyrophosphate (PC-1 knockout) hypermineralize, and some therapeutic progress could come from the discovery that inhibition of tissue nonspecific alkaline phosphatase by tetramisole improves osteoarthritic lesions caused by inorganic pyrophosphate deficiency in mice (). Other animal models could lead to a better understanding of bone physiology. For example, the effects of aromatase deficiency in androgen receptor knockout mice seem to be sex dependent. Female mice have an increase in body weight and length that could be caused by an increase in insulin-like growth factor-1 (IGF-1) levels, whereas male mice have a decreased length that can be corrected by IGF-1 ().
Hot topics Yoshiki Seino, Department of Pediatrics, Okayama University, Graduate School of Medicine and Dentistry, Okayama City, Japan New insights in the management of osteoporosisSelective estrogen receptor modulators (SERMs) are a class of compounds that can act as estrogen receptor (ER) agonists in some tissues. Currently, SERMs are used to treat and prevent breast cancer, osteoporosis, and cardiovascular disease (). Three primary SERMs — tamoxifen, toremifene, and raloxifene — are used clinically. All three have beneficial effects on bone and serum lipids and are associated with venous thromboembolism and hot flashes. New SERMs (e.g., idoxifene, droloxifene, ospemifene, lasofoxifene, and others) to treat and prevent breast cancer, osteoporosis, and cardiovascular disease are undergoing clinical development. Bolognese et al. reported a prospective, randomized, double-blind, placebo-controlled, active treatment trial to compare the safety, toleration, and efficacy of lasofoxifene versus raloxifene or placebo on bone mineral density (BMD) of the lumbar spine (L1-L4) (). At one year, lasofoxifene (0.25 mg/d) had superior effects on lumbar spine BMD and low-density lipoprotein cholesterol reduction, compared with raloxifene (60 mg/d) and placebo. The clinical success of tamoxifen and raloxifene for the prevention and treatment of breast cancer and osteoporosis, respectively, has encouraged the development of a range of new agents that target osteoporosis and other diseases.
Like parathyroid hormone, strontium ranelate (SR) is an anabolic agent that possesses unique mechanisms of action (). SR is composed of an organic moiety and two atoms of stable nonradioactive strontium. SR enhances preosteoblastic cell replication and also increases collagen and noncollagenous protein synthesis by mature osteoblast-enriched cells. These findings provide substantial evidence to categorize SR as a bone-forming agent. SR also has inhibitory effects on bone resorption (). Reginster et al. reported on the Spinal Osteoporosis Trial Intervention (SOTI) phase III study, which showed that SR reduced the risk of new vertebral fracture by 41% during a three-year study (). An early effect was also observed in the first year, with a 49% risk reduction of new vertebral fracture. The main objective of the randomized, double-blind, placebo-controlled Treatment of Peripheral Osteoporosis (TROPOS) phase III study involving 5091 postmenopausal women was to assess the efficacy of SR (2 g/d orally) for 3 years or more on new nonvertebral fracture. A secondary endpoint was femoral neck BMD change. SR significantly reduced the incidence of patients with new nonvertebral fracture in the intent-to-treat population. Risk reduction of 33% was also significant on the incidence of patients experiencing a new nonvertebral fracture in the minimal exposed data set (i.e., minimal exposure to SR during the first 18 months). A 41% reduction in the relative risk of experiencing hip fracture was also demonstrated in the minimal exposed data set. Femoral neck BMD was also increased in the SR group, with a 6.54% relative change from baseline, compared with placebo. SR is a new, effective, and safe orally administered treatment for vertebral and nonvertebral fracture in osteoporotic postmenopausal women.
Neuronal and sex hormonal regulation of bone massBody weight is known to be associated with bone mass. Hormonal factors may mediate an association of obesity with bone mass. Leptin, a hormone produced in fat tissue, has recently been shown to be inversely related to bone mass in mice. Karsenty et al. previously showed that leptin inhibits bone formation by an undefined mechanism (). Subsequent studies have led to the identification of hypothalamic groups of neurons involved in leptin's antiosteogenic function. In addition, those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Neuropeptides mediating leptin anorexigenic function did not affect bone formation. Leptin deficiency resulted in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling led to a leptin-resistant high bone mass. Conversely, beta-blockers increased bone formation and bone mass and blunted the bone loss induced by ovariectomy (). Thus, the peripheral mediator of leptin's antiosteogenic function has been identified as the sympathetic nervous system. Their study demonstrated that leptin-dependent neuronal regulation of bone formation could lead to potential therapeutic implications for osteoporosis.
Neuropeptide Y (NPY) regulates numerous physiological processes via at least five different Y receptors, but the specific roles of each receptor are still unclear. Gardiner et al. previously demonstrated that Y2 receptor knockout (KO) results in a lean phenotype, increased cancellous bone volume, and an increase in plasma pancreatic polypeptide (PP), a ligand for Y4 receptors (). PP-overexpressing mice are also known to have a lean phenotype. Deletion of the Y4 receptor also produced a lean phenotype and increased plasma PP levels. Subsequent studies compared the outcomes of NPY Y2 KO, Y4 KO, and Y2/Y4 double KO on the regulation of bone mass in the femora of four-month-old knockout and wild-type (WT) mice (). Bone mass was not altered in Y4 KO mice. Cancellous bone mass (bone volume per tissue volume [BV/TV]) was increased in Y2Y/4 KO male mice. This change was more pronounced than that observed in Y2 KO mice, suggesting synergy between Y2 and Y4 receptor pathways. However, cortical area in Y2/Y4 KO male mice was reduced, compared with Y2 KO and Y4 KO mice. Of interest, in female Y2/Y4 KO mice, there was no synergistic increase in BV/TV. Moreover, cortical area, femoral length, and mid-femoral circumference were unchanged in female Y2 KO and male Y4 KO mice, despite significant sex differences. Although the Y4 receptor pathway does not independently regulate bone mass, there is a synergistic interaction between the Y2 and Y4 pathways, which reduces cancellous bone volume and increases cortical bone mass in males. These data suggest that an interaction between the NPY pathways and sex hormone affects bone mass and is an important implication for possible interventions in obesity and for the anabolic treatment of osteoporotic bone loss.
Androgen has multiple actions on the skeleton. Androgen promotes skeletal growth and accumulation of minerals during puberty and adolescence. Androgen increases periosteal bone apposition, resulting in larger bone size and thicker cortical bone in men than in women. Aromatization to estrogens was one of the important pathways for mediating the action of testosterone on bone physiology. Estrogen is a sex steroid that regulates bone resorption in men, but both testosterone and estrogen are important in maintaining bone formation. The bone mass of males is known to be higher than that of females in both humans and mice, implying the importance of androgen signaling. Kato et al. recently established an androgen receptor (AR)-deficient mouse line (ARKO) by using a Cre/loxP system. Radiologic and histomorphometric analyses revealed that ARKO males exhibited a marked decrease in both trabecular and cortical bone volumes, with high bone turnover, compared with male and female WT littermates. However, this abnormality is not ascribable solely to the AR deficiency because ARKO males showed severe genital organ atrophy and a marked decrease in testosterone, the main androgen, which activates not only AR, but also ERs, through aromatization into estradiol. Subsequent studies by Kato et al. investigated the contributions of AR and ER impairments to the bone loss of ARKO males (). Three-week-old WT and ARKO males were orchidectomized and implanted with a slow-releasing pellet of placebo, testosterone, or dihydrotestosterone (a metabolite of testosterone) and were analyzed at eight weeks. The authors concluded that the impairment of both AR and ER signaling contributes to osteopenia in ARKO males. Bone mass of WT males is maintained by both androgen and estrogen signalings that act similarly (but independently) and is higher than that of females, which is maintained mainly by ER signaling because androgen levels are quite low.
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