Search

Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-[beta]1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-[beta]1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-[beta]1 in the bone marrow. Treatment with a TGF-[beta] type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-[beta]1 functions to couple bone resorption and formation, modulation of TGF-[beta]1 activity could be an effective treatment for bone remodeling diseases., In the adult skeleton, bone is continuously being formed and resorbed, not only to maintain mineral homeostasis but also to cope with the microfractures that occur as a consequence of [...]

Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals., Introduction Multipotent bone marrow stromal cells capable of giving rise to osteoblasts, adipocytes, and chondrocytes (a population termed mesenchymal stem/progenitor cells [MSCs]) were originally described by Friedenstein in 1966 (1), [...]

Variation in the size of structures within mature cortical bone is relevant to our understanding of apparent differences between human samples, and it is relevant to the development of histologically based age-estimation methods. It was proposed that variation may reflect effects of physical activity, through biomechanical and/or metabolic mechanisms. If these factors are local, femoral osteon area (On.Ar) should be more histologically variable than On.Ar in ribs. Ribs should show a higher variation in Haversian canal area (H.Ar) if they are sites of more remodeling activity and hence of arrested refilling of secondary osteons at time of death. This study compares On.Ar and H.Ar of secondary osteons from femora (15) and ribs (29) from 44 Holocene (Later Stone Age) foragers from South Africa (M = 19, F = 25) to values from paired femora and ribs from historic samples (Spitalfields and St. Thomas, 20 pairs from each). Fixed-effects analysis of variance demonstrates rib On.Ar to be significantly smaller than femur, but with no sex or age effects. The femur-to-rib On.Ar ratio is lower for the Holocene foragers than for the two modern samples because of relatively large rib On.Ar. Femora and ribs from the same skeleton normally show femoral On.Ar larger than rib On.Ar (37/44 pairs). Mean femoral values of On.Ar are more diverse than rib On.Ar values, but within-sample coefficients of variation are similar. Values for H.Ar are highly variable and do not reflect anatomical site, age, sex, or population effects. The patterning of osteon size does not appear to be linked to physical activity or to different rates of metabolic activity within the skeleton, at least not in a straightforward way. KEY WORDS bone remodeling; histomorphology; adult age estimation

Byline: H. Dobnig (1), L. C. Hofbauer (2), V. Viereck (3), B. Obermayer-Pietsch (1), A. Fahrleitner-Pammer (1) Keywords: Bisphosphonates; Bone mineral density; Bone turnover; Osteoporosis; Osteoprotegerin; sRANKL Abstract: Introduction Since the soluble receptor activator of the NF-IoB ligand (sRANKL) as well as the endogenous anti-resorptive cytokine osteoprotegerin (OPG) are produced by osteoblasts and given that these cells undergo significant changes during antiresorptive treatment, we hypothesized that treatment with bisphosphonates (BP) would be accompanied by changes in serum OPG and sRANKL levels. Methods In a prospective, randomized controlled trial of previously untreated postmenopausal women with osteoporosis, oral BP therapy (daily doses of either 10 mg alendronate or 5 mg risedronate) in combination with calcium/vitamin D was compared to calcium/vitamin D treatment alone (control group). Follow-up at 2, 6 and 12 months was completed for 56 patients. Standardized spinal X-rays were performed at baseline, and DEXA measurements at the femoral neck and trochanter were made at baseline and after 1 year. Serum OPG and sRANKL levels were measured with a polyclonal antibody-based ELISA system. Results After 1 year, there was a non-significant loss in neck and trochanteric bone mineral density (BMD) in the CTR group and a mean increase of 3.3% and 4.6% in the combined BP group (both p&lt 0.0001), respectively. Serum levels of C-terminal telopeptides of type I collagen (sCTX) and osteocalcin decreased by 12% and 10% at 12 months in the CTR group and by 43% and 23% in the combined BP group, respectively (all significant). OPG serum levels in the CTR group decreased significantly by 9% at 2 months (p&lt 0.005) and remained below pre-treatment levels at later time points. Both the alendronate- and risedronate-treated patient groups showed unaltered OPG levels after 2 months, but they had significantly increased serum levels at 6 and 12 months. Levels of sRANKL were unchanged throughout the treatment period. Univariate regression analysis demonstrated that changes in serum OPG levels after 12 months of BP treatment were positively and better correlated to BMD changes (trochanter: r= 0.59, p&lt 0.0001 neck: r= 0.50, p&lt 0.001) than those of sCTX, which showed the expected negative correlation to BMD change (trochanter: r= --0.35, p=0.03 neck: r= --0.23, p=0.16). With multiple regression analyses at 12 months, R.sup.2 values for 1-year changes in trochanteric BMD of 0.33 (OPG alone) and 0.23 (sCTX alone) were significantly improved to the 0.57 when OPG and sCTX changes were combined (p&lt 0.001). Results for the femoral neck were also statistically significant R.sup.2=0.35, p&lt 0.001). BMD and OPG changes in the CTR group were not correlated with each other. Conclusions We conclude that with BP treatment, changes in serum OPG levels, unlike changes in sCTX levels, are positively correlated to changes in BMD response. The BP-related changes in serum OPG levels during treatment could result from effects on osteoclastogenesis and osteoclast apoptosis as well as from a direct stimulatory effect on osteoblastic OPG production. These changes in OPG levels may be used to predict the individual response of patients to BP treatment. Author Affiliation: (1) Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University Graz, Auenbruggerplatz 15, 8036, Graz, Austria (2) Division of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany (3) Department of Obstetrics and Gynecology, Georg-August University, Goettingen, Germany Article History: Registration Date: 31/10/2005 Received Date: 24/03/2005 Accepted Date: 24/10/2005 Online Date: 25/01/2006

Current therapies for delayed- or nonunion bone fractures are still largely ineffective. Previous studies indicated that the VEGF homolog placental growth factor (PlGF) has a more significant role in disease [...]

The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB[2.sup.-/-] phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-[kappa]B ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries. bone remodeling | HU-308 | osteoblast | osteoclast

New taphonomic data on the Sterkfontein Member 4 (South Africa) fossil hominid assemblage are presented. The previous estimate of hominid individuals represented in the deposit (45) is increased to 87. New minimum numbers of hominid skeletal elements are provided, and incidences of bone surface damage inflicted by prehistoric biological agents are summarized. The hominid sample from Member 4 is composed predominately of gnathic remains and has a paucity of postcrania. This dearth of postcrania limits, to some extent, inferences about the formation of the Sterkfontein assemblage. However, carnivore tooth marks on some fossil specimens and an overall broad similarity in patterns of skeletal part representation between Sterkfontein and primate bone assemblages created by extant carnivores suggest that carnivores did have some involvement in the accumulation of the fossil hominid assemblage. Thus, this study provides support for the 'carnivore-collecting hypothesis' of Brain ([1981] The Hunters or the Hunted? Chicago: University of Chicago Press), which implicates large carnivores as prominent collecting agents of hominid body parts in Sterkfontein Member 4. Evidence of bone surface damage is, however, too scant to make confident inferences about specific carnivore taxon/taxa involved in hominid bone collection at the site. KEY WORDS Australopithecus; MNI; MNE; bone surface damage; 'carnivore-collecting hypothesis'

Byline: H. P. Bhattoa (1), P. Bettembuk (1), A. Balogh (1), G. Szegedi (2), E. Kiss (2) Keywords: Biochemical markers of bone turnover; Bone mineral density; Osteopenia; Postmenopausal; Systemic lupus erythematosus; Transdermal estrogen replacement therapy Abstract: We studied the effect of 1-year transdermal estrogen replacement therapy (ERT) on bone mineral density (BMD) and biochemical markers of bone turnover in osteopenic postmenopausal systemic lupus erythematosus (SLE) patients in a randomized, double-blind, placebo-controlled trial. SLE patients were randomly allocated to treatment (estradiol 50 ug transdermal 17[beta]-estradiol n=15) or placebo (n=17) group. Both groups received 5 mg continuous oral medroxyprogesterone acetate, 500 mg calcium and 400 IU vitamin D.sub.3. L.sub.1--L.sub.4 spine (LS), left femur and total hip BMD were measured at baseline and at 6 and 12 months. Serum osteocalcin (OC) and degradation products of C-terminal telopeptides of type-I collagen (CTx) levels were measured at baseline and 3, 6, 9, and 12 months. There was a significant difference in the percentage change of LS BMD at 6 months between the two groups (103.24+-3.74% (estradiol group) vs 98.99+-3.11% (placebo group) P&lt 0.005). There was a significant decrease within the estradiol group in the CTx levels between baseline and all subsequent visits (P&lt 0.05). There was no significant difference in SLE disease activity index, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) damage index and corticosteroid dose during the study period. Transdermal estradiol may prevent bone loss in postmenopausal SLE women at the lumbar spine and femur, with no increase in disease activity among postmenopausal SLE women receiving transdermal ERT. The high dropout rate (8/15) leads us to the conclusion that efficacy of HRT in a high-risk group such as SLE women can be attained only in a small number of patients, provided all inclusion/exclusion criteria are strictly adhered to. Author Affiliation: (1) Regional Osteoporosis Center, Department of Obstetrics and Gynecology, Medical and Health Science Center, University of Debrecen, Nagyerdei Krt. 98, 4012, Debrecen, Hungary (2) Immunology Department, 3rd Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Article History: Registration Date: 10/11/2003 Received Date: 03/03/2003 Accepted Date: 28/10/2003 Online Date: 16/12/2003

Byline: A. I. A. Rahmy (1), T. Gosens (2), G. M. Blake (3), A. Tonino (2), I. Fogelman (3) Keywords: Bone mineral density; Bone quality; Dual energy X-ray absorptiometry; Periprosthetic bone loss; Total hip arthroplasty Abstract: Periprosthetic bone loss is a major cause of concern in patients undergoing total hip arthroplasty (THA). Further studies are required to identify the factors determining the pattern of bone remodelling following THA and obtain improvements in the design and durability of prostheses. In this study, we monitored periprosthetic bone loss around two different types of hydroxyapatite coated femoral implant over a 3-year period to evaluate their design and investigate the relationship with the preoperative bone mineral density (BMD) at the spine, hip and forearm. Sixty patients (35 F, 25 M, mean age 63 years, range 46--75 years) undergoing THA were randomised to either the Anatomic Benoist Girard (ABG) or Mallory-Head (MH) femoral stem. Preoperative dual-energy X-ray absorptiometry (DXA) scans were acquired of the posteroanterior (PA) and lateral lumbar spine, the contralateral hip and the non-dominant forearm. Postoperative DXA scans were performed to measure periprosthetic BMD at 10 days (treated as baseline), 6 weeks, and 3, 6, 12, 24 and 36 months after THA using a standard Gruen zone analysis. Results were expressed as the percentage change from baseline and the data examined for the differences in bone loss between the different Gruen zones, between the ABG and MH stems, and the relationship with preoperative BMD. A total of 50 patients (24 ABG, 26 MH) completed the study. Three months after THA there was a statistically significant BMD decrease in every Gruen zone that varied between 5.6% and 13.8% for the ABG prosthesis and between 3.8% and 8.7% for the MH prosthesis. Subsequently, in most zones BMD reached a plateau or showed a small recovery. However, BMD continued to fall in Gruen zones 1 and 7 in ABG patients and Gruen zone 1 in MH patients. Bone loss was less in every Gruen zone in MH patients compared with ABG with the largest difference (10%, P=0.018) in Gruen zone 7. Highly significant relationships were found between periprosthetic bone loss and preoperative BMD measured at the PA spine (P&lt 0.001), total hip (P=0.004) and total distal radius (P&lt 0.001). This study showed differences between two different designs of hydroxyapatite-coated implant that confirmed that prosthesis design influences periprosthetic bone loss. The study also showed that patients' bone density measured at the spine, hip or forearm at the time of operation was a major factor influencing bone loss around the femoral stem. Author Affiliation: (1) Department of Nuclear Medicine, Atrium Medical Centre, Heerlen, The Netherlands (2) Department of Orthopaedics, Atrium Medical Centre, Heerlen, The Netherlands (3) Department of Nuclear Medicine, Guy's Hospital, St Thomas Street, London, SE1 9RT, United Kingdom Article History: Registration Date: 15/10/2003 Received Date: 27/05/2003 Accepted Date: 06/10/2003 Online Date: 06/12/2003

Byline: Christian Meier (1,2), Muller Beat (1), Merih Guglielmetti (1), Mirjam Christ-Crain (1), Jean-Jacques Staub (1), Marius Kraenzlin (1) Keywords: Bone density; Bone remodeling; Replacement; Subclinical hypothyroidism; Thyroxine Abstract: This study evaluated the effect of physiological l-thyroxine (L-T4) treatment on bone metabolism in patients with subclinical hypothyroidism. Sixty-six women with subclinical hypothyroidism (TSH 11.7 +- 0.8 mIU/l) were randomly assigned to receive L-T4 or placebo for 48 weeks. Sixty-one of 66 patients completed the study. Individual L-T4 replacement (mean dosage 85.5 +- 4.3 ug/day) was performed targeting euthyroid thyroid-stimulating hormone (TSH) levels. The primary outcome measure was 24- and 48-week change in markers of bone formation (total and bone alkaline phosphatase [ALP, bone ALP], osteocalcin [OC]) and resorption (pyridinoline [PYD] and deoxypyridinoline [DPD], C-terminal cross-linking telopeptide type I [CTX]). Secondary outcomes were 48-week changes in bone mineral density (BMD) of the lumbar spine and hip, measured by dual-energy X-ray absorptiometry. Compared with placebo, l-thyroxine (n=31) resulted in significant activation of bone turnover. Overall, a significant treatment effect was observed for DPD (between-group difference 16.0% 95%CI, 10.9 to 21.1), CTX (29.9% 95%CI, 23.3 to 36.5), and bone ALP (13.2% 95%CI, 6.6 to 19.7) after 24 weeks. At the end of the study, lumbar BMD in the both treatment groups differed by 1.3% (95%CI, -2.9 to 0.5) with lower levels in l-thyroxine treated women. Significant difference in BMD between groups was also observed at the trochanter. We conclude that physiological l-thyroxine treatment accelerates bone turnover reflecting early activation of bone remodeling units in the initial replacement of subclinical hypothyroidism. The observed bone loss could be interpreted as an adaptive mechanism on decreased bone turnover in preexistent hypothyroidism, and not as l-thyroxine-induced clinically important bone loss. However, long-term studies are needed to confirm this assumption. Author Affiliation: (1) Division of Endocrinology, Department of Medicine, University Hospitals, CH-4031, Basel, Switzerland (2) Bone Research Laboratory, ANZAC Research Institute, University of Sydney, NSW 2139, Concord, Australia Article History: Registration Date: 23/09/2003 Received Date: 24/03/2003 Accepted Date: 12/09/2003 Online Date: 16/01/2004 Article note: This work was supported by grants from the Swiss National Science Foundation (32.27866.89, 32.37792.93, and 32.37792.98) and unconditional research grants from Henning Berlin, Sandoz Research, and Roche Research foundations. Presented in part at the 24th annual meeting of the American Society for Bone and Mineral Research, San Antonio, 2002, and at the 84th annual meeting of The Endocrine Society, San Francisco, 2002.

Byline: V. Camozzi (1), F. Lumachi (2), F. Mantero (1), M. Piccolo (1), G. Luisetto (1) Keywords: Bone densitometry; Bone metabolism; Parathyroid hormone; Primary hyperparathyroidism; Quantitative ultrasound Abstract: Fifty-one patients with surgically proven primary hyperparathyroidism (PHPT), 11 males and 40 females, mean age+-SD: 55.9+-14.1 years, and 58 age- and sex-matched normal subjects were studied. The femoral and L.sub.2--L.sub.4 bone mineral density (BMD Hologic QDR 4500 C), as well as quantitative ultrasonometry (QUS DBM-Sonic 1200) of the phalanges of both hands were measured in patients and controls. QUS measurements included amplitude-dependent speed of sound (AD-SoS), and other parameters derived from the graphic trace: signal dynamics (Sdy), first wave amplitude (FWA), bone transmission time (BTT) and ultrasound bone profile index (UBPI). Patients with PHPT showed significantly lower dual energy X-ray densitometry (DXA) values and QUS parameters compared to controls (lumbar spine Z-score: controls: -0.16+-1.12, PHPT: -0.70+-1.14, P=0.016 femoral neck Z-score: controls: -0.28+-1.74, PHPT: -1+-1.01, P=0.013 total femur Z-score: controls: -0.33+-1.12, PHPT: -1.01+-0.95, P=0.0013 AD-SoS Z-score: controls: -0.89+-1.22, PHPT: -1.97+-1.78, P=0.0003 FWA Z-score: controls: 0.36+-1, PHPT: 0.62+-0.85, P&lt 0.0001 BTT Z-score: controls: 0.04+-1.03, PHPT: -0.45+-1.37, P=0.044 UBPI Z-score: controls: -0.02+-1.01, PHPT: -0.68+-1.05, P=0.002 SDy (mV/us.sup.2): controls: -295+-256, PHPT: -498+-306, P=0.0003). In male patients, BMD values measured on the lumbar spine and femoral regions were similar to those found in male controls, while QUS values were significantly lower (lumbar spine Z-score: controls: -1.05+-1.41, PHPT: -1.75+-1.21, P=0.21 femoral neck Z-score: controls: -0.37+-1.84, PHPT: -1.11+-1.14, P=0.27 total femur Z-score: controls: -0.16+-1.59, PHPT: -1.02+-1.20, P=0.168 AD-SoS Z-score: controls: -0.52+-1.58, PHPT: -1.57+-1.77, P=0.149 FWA Z-score: controls: 0.67+-1.01, PHPT: -0.74+-0.79, P=0.0016 BTT Z-score: controls: 1.22+-0.83, PHPT: 0.75+-1.51, P=0.478 UBPI Z-score: controls: 0.56+-0.94, PHPT: -0.47+-1.10, P=0.025 SDy (mV/us.sup.2): controls: -167+-230, PHPT: -485+-307, P=0.01). Women with PHPT were further divided into two subgroups: premenopause (n=11) and postmenopause (n=29). The premenopausal women with PHPT showed significantly lower DXA values than those of the premenopausal control ones, but similar QUS parameters (lumbar spine Z-score: controls: 0.12+-0.66, PHPT: -0.59+-0.85, P=0.03 femoral neck Z-score: controls: 0.06+-2.85, PHPT: -1.48+-1.05, P=0.11 total femur Z-score: controls: -0.51+-0.97, PHPT: -1.48+-0.63, P=0.009 AD-SoS Z-score: controls: 0.78+-0.89, PHPT: -1.26+-1.88, P=0.42 FWA Z-score: controls: 1.14+-0.77, PHPT: 0.12+-0.80, P=0.007 BTT Z-score: controls: 0.13+-0.60, PHPT: 0.25+-1.15, P=0.757 UBPI Z-score: controls: 0.73+-0.49, PHPT: 0.24+-0.96, P=0.15 SDy (mV/us.sup.2): controls: -118+-123, PHPT: -271+-301, P=0.106). The postmenopausal women with PHPT showed both DXA and QUS parameters significantly lower than those found in the postmenopausal controls (lumbar spine Z-score: controls: 0.09+-0.96, PHPT: -0.31+-0.96, P=0.004 femoral neck Z-score: controls: -0.38+-1.01, PHPT: -0.76+-0.91, P=0.14 total femur Z-score: controls: -0.33+-0.97, PHPT: -0.81+-0.92, P=0.057 AD-SoS Z-score: controls: -1.08+-1.17, PHPT: -2.38+-1.68, P=0.31 FWA Z-score: controls: -0.013+-0.81, PHPT: -0.86+-0.74, P=0.0009 BTT Z-score: controls: -0.58+-0.68, PHPT: -1.13+-0.93, P=0.016 UBPI Z-score: controls: -0.62+-0.83, PHPT: -1.11+-0.82, P=0.034 SDy (mV/us.sup.2): controls: -419+-242, PHPT: -589+-269, P=0.012). The relative risk of osteopenia was significantly increased in PHPT patients at several measurement sites. There was a highly significant correlation between spine and femoral BMD and QUS parameters, while PTH serum levels did not correlate with any of the densitometric variables. In conclusion, QUS parameters would seem to be able to distinguish patients with PHPT from normal controls in male subjects and in postmenopausal women, but not in premenopausal women. This would suggest that the higher estrogen levels in premenopausal patients might preserve the bone from significant structural changes. This may also suggest that hyperparathyroidism, in addition to the reduction of bone mineral content, can cause an alteration of bone structure with an additional increase in fracture risk in postmenopausal women. Furthermore, the alterations in QUS parameters in patients who do not show significant changes in DXA measurements suggest an involvement of bone that is independent of mineral content and may be helpful for selecting candidates for surgery, according to NIH criteria. Author Affiliation: (1) Department of Medical and Surgical Sciences, Division of Endocrinology, University of Padua, Via Ospedale 105, I-35128, Padua, Italy (2) Department of Surgical and Gastroenterological Sciences, Endocrine Surgery Unit, University of Padua, Padua, Italy Article History: Received Date: 24/05/2002 Accepted Date: 14/02/2003 Online Date: 29/04/2003

Byline: S. Migliaccio (1), J. J. B. Anderson (2) Keywords: Bone markers; Bone mineral density; Epidemiology; Isoflavones (genistein and daidzein); Osteoblasts; Osteoporosis Abstract: A review of the recent literature on the effects of isoflavones was undertaken to determine whether molecules such as genistein and daidzein, aglycone derivatives of soybeans, might have benefit in the prevention and treatment of osteoporosis. The current standard for science-based medicine is the documentation of efficacy of an agent under controlled, randomized, prospective conditions. A few short clinical investigations have been undertaken using isoflavones (along with soy protein), but they had limitations in study design, and the numbers of women studied were small. Other evidence from animal models, in vitro experiments, and epidemiological reports suggest that the isoflavones have skeletal benefits in women with little or no ovarian estrogen production. A clear need exists for prospective human trials, using the required conditions of randomized clinical trials and designs, to satisfy objectively the needs for science-based medicine and for appropriate clinical applications. Author Affiliation: (1) Department of Medical Physiopathology, University of La Sapienza, Rome, Italy (2) Department of Nutrition, Schools of Public Health and Medicine, University of North Carolina, Chapel Hill, NC 27599, USA Article History: Received Date: 24/10/2001 Accepted Date: 29/11/2002 Online Date: 29/04/2003

Byline: D. C. Bauer (1,2) Keywords: BMP-2; HMG CoA reductase inhibitors; Osteoporosis; Statins Abstract: Recent studies suggest that the mevalonate pathway plays an important role in skeletal metabolism. HMG CoA reductase inhibitors ('statins'), which inhibit a key enzyme in the mevalonate pathway, are widely used for the treatment of hyperlipidemia. In vitro and animal studies demonstrate that statins stimulate the production of BMP-2, a potent regulator of osteoblast differentiation and activity, suggesting that statins may have an anabolic effect on bone. Statin use in most, but not all observational studies is associated with a reduced risk of fracture, particularly hip fracture, even after adjustment for the confounding effects of age, weight and other medication use. This beneficial effect has not been observed in clinical trials designed to assess cardiovascular endpoints. The effects of statins on bone mass and bone turnover are controversial, but increased bone mass and reduced bone turnover have been observed in controlled studies. Further studies of the skeletal effects of statins are needed, particularly their effects on surrogate markers such as bone mass, bone turnover, and microarchitecture, to determine the optimal formulation, dosing and route of administration. Clinical trials with fracture endpoints are needed before statins can be recommended as therapeutic agents for osteoporosis. Author Affiliation: (1) Department of Medicine, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA (2) 74 New Montgomery, Suite 600, San Francisco, CA 94105, USA Article History: Received Date: 28/01/2002 Accepted Date: 10/09/2002 Online Date: 08/05/2003

To isolate high-quality human postnatal stem cells from accessible resources is an important goal for stem-cell research. In this study we found that exfoliated human deciduous tooth contains multi-potent stem cells [stem, cells from human exfoliated deciduous teeth (SHED)]. SHED were identified to be a population of highly proliferative, clonogenic cells capable of differentiating into a variety of cell types including neural cells, adipocytes, and odontoblasts. After in vivo transplantation, SHED were found to be able to induce bone formation, generate dentin, and survive in mouse brain along with expression of neural markers. Here we show that a naturally exfoliated human organ contains a population of stem cells that are completely different from previously identified stem cells. SHED are not only derived from a very accessible tissue resource but are also capable of providing enough cells for potential clinical application. Thus, exfoliated teeth may be an unexpected unique resource for stem-cell therapies including autologous stem-cell transplantation and tissue engineering. odontoblast | bone regeneration | neural differentiation | adipocyte | dental pulp stern cell