IBMS BoneKEy | Not To Be Missed
Clinical and basic research papers – December 2007 selections
DOI:10.1138/20080292
Bone modeling and remodeling◆ McGee ME, Maki AJ, Johnson SE, Nelson OL, Robbins CT, Donahue SW. Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis). Bone. 2007 Oct 25; [Epub ahead of print]
Disuse uncouples bone formation from resorption, leading to increased porosity and decreased bone geometrical properties. Black bears have decreased cortical bone turnover during hibernation with balanced formation and resorption in femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. Bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears. —ES
Epidemiology◆ Finkelstein JS, Brockwell SE, Mehta V, Greendale GA, Sowers MR, Ettinger B, Lo JC, Johnston JM, Cauley JA, Danielson ME, Neer RM. Bone mineral density changes during the menopause transition in a multi-ethnic cohort of women. J Clin Endocrinol Metab. 2007 Dec 26; [Epub ahead of print]
Does peri- and post-menopausal bone loss differ by race? This large, multi-ethnic cohort study shows that bone loss is indeed greater in Asians than Caucasians and lowest in African-Americans. Most interestingly, however, most of these differences could be accounted for by differences in weight, the BMD decline being 30-50% less in the heaviest women. —SF
Pathophysiology◆ Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, Thomas JT, Luyten FP. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum. 2007 Dec;56(12):4095–103.
Polymorphisms in the FRZB gene, a secreted WNT antagonist, is associated with osteoarthritis. Targeted deletion of the Frzb gene in mice increased articular cartilage loss during arthritis triggered by instability, enzymatic injury, or inflammation. Cartilage damage in Frzb(-/-) mice was associated with increased WNT signaling and matrix metalloproteinase 3 (MMP-3) expression and activity. Frzb(-/-) mice had increased cortical thickness and density, stiffness, and periosteal anabolic response to mechanical loading. Loss of Frzb may contribute to cartilage damage by increasing the expression and activity of MMPs, in a WNT-dependent and WNT-independent manner. This may contribute to the development of osteoarthritis by producing increased strain on the articular cartilage during normal locomotion but may protect against osteoporosis. —ES
◆ Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, Xie Y, Drezner MK. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest. 2008 Jan 2; [Epub ahead of print]
Recent studies have started to highlight the role played by osteoblastic cells in the regulation of phosphate metabolism. Whether an osteoblast-specific defect in some component of the phosphate regulatory pathway is sufficient to cause hypophosphatemia, however, remains unclear. The authors generated both a global and osteoblast-specific KO mouse of Phex. Their findings indicate very similar phenotypes in both KO mice and in Hyp mice, including an increase of bone and circulating FGF-23, a decreased expression of the NaPi II renal transporter, and osteomalacia. Hence osteoblastic PHEX seems both necessary and sufficient to regulate phosphate homeostasis by phosphatonins. —SF
Treatment and drug effects◆ Bonnelye E, Chabadel A, Saltel F, Jurdic P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone. 2008 Jan;42(1):129–38.
Considering the ongoing controversy about the mode of action of strontium ranelate (SrR) on bone, this paper is of interest as it consistently demonstrates, through the use of standard laboratory procedures, dual effects of the drug in mouse primary cells. Hence expression of osteoblast differentiation markers and nodule mineralization was increased whereas osteoclastogenesis and bone resorbing activity in vitro was decreased dose-dependently by SrR. One may only regret the absence of calcium in the control group. —SF
◆ Boonen S, Marin F, Obermayer-Pietsch B, Simões ME, Barker C, Glass EV, Hadji P, Lyritis G, Oertel H, Nickelsen T, McCloskey EV; for the EUROFORS Investigators. Effects of prior antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2007 Dec 26; [Epub ahead of print]
Whether PTH effects on bone turnover and BMD will be similar in the actual clinical setting of patients previously treated with anti-resorptives and in treatment-naive patients, as included in the pivotal PTH studies, remains unclear. The common practice of a “drug holiday” between antiresorptives and PTH also remains empirical. This prospective, open-label study clarifies some of these issues by demonstrating that in postmenopausal women with established osteoporosis and previously treated with an anti-resorptive, mainly a bisphosphonate, for at least 12 months, PINP nearly doubled within 1 month of teriparatide therapy, whereas spine BMD increased progressively from 6 to 24 months, eventually reaching 9 to 13% above baseline. However, this study also confirms that BMD at the hip decreases early after initiation of teriparatide, which could be due to a reversal of the higher degree of mineralization induced by anti-resorptives once bone turnover is accelerated by PTH. —SF
◆ Cartsos VM, Zhu S, Zavras AI. Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. J Am Dent Assoc. 2008 Jan;139(1):23–30.
This analysis concerning the risk of ONJ in 714,217 patients with osteoporosis or cancer (breast, lung, prostate and myeloma) was performed on a large healthcare database of 15 million members in the US and based on ICD diagnostic codes for inflammatory conditions of the jaw (incl. ONJ); for major jaw surgery necessitated by necrotic or inflammatory indications; and for jaw surgeries necessitated by a malignant process. The design of this study is similar to some recent analyses of the effects of corticosteroids or beta-blockers on fracture risk, and analyses of drug effectiveness in osteoporosis (the REAL study). Here, odds ratios for ONJ and Co. were increased 4- to 8-fold among both patients with osteoporosis, and those with cancer, receiving intravenous bisphosphonates, but reduced up to 35% in those receiving oral bisphosphonates for osteoporosis. On the other hand, the pivotal zoledronate trials did not report an increased risk of ONJ over three years. Hence the jury is still out… —SF
◆ Lekander I, Borgström F, Ström O, Zethraeus N, Kanis JA. Cost effectiveness of hormone therapy in women at high risks of fracture in Sweden, the US and the UK-Results based on the Women's Health Initiative randomised controlled trial. Bone. 2007 Oct 23; [Epub ahead of print]
The cost-effectiveness of estrogen treatment in 50-year-old women was assessed based on a societal perspective and evidence in the Women's Health Initiative (WHI) trials. Hormone therapy (HT) compared to no treatment was cost-effective for most sub-groups of hysterectomized women, whereas for women with an intact uterus without a previous fracture, HT was dominated by no treatment. Fracture risks were the single most important determinant of cost-effectiveness. HT is cost-effective in women with a hysterectomy irrespective of prior fracture status. In women with an intact uterus, opposed HT was cost-effective in those with a prior vertebral fracture, but cost-ineffective in women without a prior vertebral fracture. Even though HT is found cost-effective for a selection of osteoporotic women, it is unlikely to be considered for first-line therapy for osteoporosis because bisphosphonates have shown a similar reduction in fracture risks but without an increased risk of adverse events. —ES
◆ Recker RR, Delmas PD, Halse J, Reid IR, Boonen S, García-Hernandez PA, Supronik J, Lewiecki EM, Ochoa L, Miller P, Hu H, Mesenbrink P, Hartl F, Gasser J, Eriksen EF. Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. J Bone Miner Res. 2008 Jan;23(1):6–16.
Cross-sectional analysis of quite a large number of iliac crest bone biopsies (n=152) obtained after 3 years of zoledronate treatment or placebo indicates improvement of bone microarchitecture and the expected decrease of bone turnover indices, without evidence of a defect in osteoid formation or mineralization. Rather, mineral apposition rate was significantly higher in ZOL compared to PBO, an intriguing and quite novel observation regarding bisphosphonate therapy. —SF
Reviews, perspectives and editorials◆ Greenspan SL. Approach to the prostate cancer patient with bone disease. J Clin Endocrinol Metab. 2008 Jan;93(1):2–7.
◆ Rosen CJ. Bone remodeling, energy metabolism, and the molecular clock. Cell Metab. 2008 Jan;7(1):7–10.
◆ Ruggiero SL, Woo SB. Bisphosphonate-related osteonecrosis of the jaws. Dent Clin North Am. 2008 Jan;52(1):111–28.
◆ Zehnacker C, Bemis-Dougherty A. Effect of weighted exercises on bone mineral density in post menopausal women: a systematic review. J Geriatr Phys Ther. 2007;30(2):79.
Other studies of potential interest◆ Adami S, San Martin J, Muñoz-Torres M, Econs MJ, Xie L, Dalsky GP, McClung M, Felsenberg D, Brown JP, Brandi ML, Sipos A. Effect of raloxifene after recombinant teriparatide [hPTH(1-34)] treatment in postmenopausal women with osteoporosis. Osteoporos Int. 2008 Jan;19(1):87–94.
◆ Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008 Jan 1;68(1):92–104.
◆ Cho K, Demissie S, Dupuis J, Cupples LA, Kathiresan S, Beck TJ, Karasik D, Kiel DP. Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans. Bone. 2008 Jan;42(1):53–60.
◆ Ding KH, Shi XM, Zhong Q, Kang B, Xie D, Bollag WB, Bollag RJ, Hill W, Washington W, Mi QS, Insogna K, Chutkan N, Hamrick M, Isales CM. Impact of glucose-dependent insulinotropic peptide on age-induced bone loss. J Bone Miner Res. 2007 Dec 11; [Epub ahead of print]
◆ Espina B, Liang M, Russell RG, Hulley PA. Regulation of bim in glucocorticoid-mediated osteoblast apoptosis. J Cell Physiol. 2007 Dec 6; [Epub ahead of print]
◆ Frankel BM, Monroe T, Wang C. Percutaneous vertebral augmentation: an elevation in adjacent-level fracture risk in kyphoplasty as compared with vertebroplasty. Spine J. 2007 Sep-Oct;7(5):575–82.
◆ Hodgson JM, Devine A, Burke V, Dick IM, Prince RL. Chocolate consumption and bone density in older women. Am J Clin Nutr. 2008 Jan;87(1):175–80.
◆ Kanis JA, Adams J, Borgström F, Cooper C, Jönsson B, Preedy D, Selby P, Compston J. The cost-effectiveness of alendronate in the management of osteoporosis. Bone. 2008 Jan;42(1):4–15.
◆ Kondo T, Kitazawa R, Yamaguchi A, Kitazawa S. Dexamethasone promotes osteoclastogenesis by inhibiting osteoprotegerin through multiple levels. J Cell Biochem. 2008 Jan 1;103(1):335–45.
◆ Lafont JE, Talma S, Hopfgarten C, Murphy CL. Hypoxia promotes the differentiated human articular chondrocyte phenotype through sox9-dependent and independent pathways. J Biol Chem. 2007 Dec 12; [Epub ahead of print]
◆ Laudisio A, Marzetti E, Antonica L, Cocchi A, Bernabei R, Zuccalà G. Association of left ventricular function with bone mineral density in older women: a population-based study. Calcif Tissue Int. 2008 Jan 4; [Epub ahead of print]
◆ Lucas GJ, Riches PL, Hocking LJ, Cundy T, Nicholson GC, Walsh JP, Ralston SH. Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent. J Bone Miner Res. 2008 Jan;23(1):58–63.
◆ Makareeva E, Mertz EL, Kuznetsova NV, Sutter MB, Deridder AM, Cabral WA, Barnes AM, McBride DJ, Marini JC, Leikin S. Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta. J Biol Chem. 2007 Dec 11; [Epub ahead of print]
◆ Matsumoto T, Kano K, Kondo D, Fukuda N, Iribe Y, Tanaka N, Matsubara Y, Sakuma T, Satomi A, Otaki M, Ryu J, Mugishima H. Mature adipocyte-derived dedifferentiated fat cells exhibit multilineage potential. J Cell Physiol. 2007 Dec 6; [Epub ahead of print]
◆ Miller PD, Epstein S, Sedarati F, Reginster JY. Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. Curr Med Res Opin. 2008 Jan;24(1):207–13.
◆ Poree B, Kypriotou M, Chadjichristos C, Beauchef G, Renard E, Legendre F, Melin M, Gueret S, Hartmann DJ, Mallein-Gerin F, Pujol JP, Boumediene K, Galera P. Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of SP1/SP3 ratio and of the binding activity of both factors to the COL2A1 promoter. J Biol Chem. 2007 Dec 7; [Epub ahead of print]
◆ Raggatt LJ, Qin L, Tamasi J, Jefcoat SC Jr, Shimizu E, Selvamurugan N, Liew FY, Bevelock L, Feyen JH, Partridge NC. IL-18 is regulated by parathyroid hormone and is required for its bone-anabolic actions. J Biol Chem. 2007 Dec 28; [Epub ahead of print]
◆ Rejnmark L, Vestergaard P, Hermann AP, Brot C, Eiken P, Mosekilde L. Dietary intake of folate, but not vitamin B(2) or B(12), is associated with increased bone mineral density 5 years after the menopause: results from a 10-year follow-up study in early postmenopausal women. Calcif Tissue Int. 2008 Jan 4; [Epub ahead of print]
◆ Yang M, Birnbaum MJ, Mackay CA, Mason-Savas A, Thompson B, Odgren PR. Osteoclast stimulatory transmembrane protein (OC-STAMP), a novel protein induced by RANKL that promotes osteoclast differentiation. J Cell Physiol. 2007 Dec 6; [Epub ahead of print]
◆ Yu S, Jiang Y, Galson DL, Luo M, Lai Y, Lu Y, Ouyang HJ, Zhang J, Xiao G. General transcription factor IIA-gamma increases osteoblast-specific Osteocalcin gene expression via activating transcription factor 4 and runt-related transcription factor 2. J Biol Chem. 2008 Jan 2; [Epub ahead of print]
◆ Zaidi SK, Pande S, Pratap J, Gaur T, Grigoriu S, Ali SA, Stein JL, Lian JB, van Wijnen AJ, Stein GS. Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19861–6.
◆ Zaiss MM, Axmann R, Zwerina J, Polzer K, Gückel E, Skapenko A, Schulze-Koops H, Horwood N, Cope A, Schett G. Treg cells suppress osteoclast formation: A new link between the immune system and bone. Arthritis Rheum. 2007 Dec;56(12):4104–12.
◆ Zhang W, Yang N, Shi XM. Regulation of MSC osteogenic differentiation by glucocorticoid-induced leucine zipper (GILZ). J Biol Chem. 2007 Dec 14; [Epub ahead of print]
◆ Zhang ZL, He JW, Qin YJ, Hu YQ, Li M, Zhang H, Hu WW, Liu YJ, Gu JM. Association between myostatin gene polymorphisms and peak BMD variation in Chinese nuclear families. Osteoporos Int. 2008 Jan;19(1):39–47.
◆ Zhou H, Mak W, Zheng Y, Dunstan CR, Seibel MJ. Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through WNT signaling. J Biol Chem. 2007 Nov 28; [Epub ahead of print]
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