BoneKEy-Osteovision | Not To Be Missed

Clinical and basic research papers: September 2003 selections

DOI:10.1138/2003100

Bone modeling and remodeling

◆ Aszodi A, Hunziker EB, Brakebusch C, Fassler R. b1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis. Genes Dev. 2003 Oct 1;17(19):2465–79.

Deletion of the b1-integrin gene in chondrocytes does not prevent their condensation, but produces a severe chondrodystrophy in which the growth plates are disorganized and chondrocyte proliferation is progressively impaired. Increased levels of nuclear Stat-1 and increased expression of p16 and p21 are found in mutant limb buds, suggesting a role for fibroblast growth factor receptor 3 in the proliferation defect. The density of type II collagen fibrils is reduced, and binucleate chondrocytes are commonly present because of a defect in cytokinesis. —GJS

◆ Ferguson VL, Ayers RA, Bateman TA, Simske SJ. Bone development and age-related bone loss in male C57BL/6J mice. Bone. 2003 Sep;33(3):387–98.

This is a nice study because it compacts the whole of life, and the rise and fall of bone structural features can be seen with a bird's eye view. Note how there is little time of stability — life is a roller coaster, up then down. Studies of bone formation and resorption across life are provided at the tissue level, but not at the cellular level. The latter is needed.

Pathophysiology

◆ Lean JM, Davies JT, Fuller K, Jagger CJ, Kirstein B, Partington GA, Urry ZL, Chambers TJ. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest. 2003 Sep;112(6):915–23.

Antioxidant levels are decreased by estrogen lack and restored by estrogen. Inhibitors of reactive oxygen species block bone loss after ovariectomy, and inhibition of antioxidant synthesis induces bone loss. One locus of these effects is the osteoclast. 17-b estradiol modulates the osteoclastic thiol antioxidant system, but indirect effects of reactive oxygen species on osteoclast activation by cytokines are also possible. The results open up a new direction in the study of postmenopausal estrogen treatment of osteoporosis. —GJS

◆ Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003 Sep 26;278(39):37419–26.

Fibroblast growth factor 23 (FGF23) is the phosphatonin that causes phosphate wasting in tumor-induced osteomalacia and autosomal dominant hypophosphatemic rickets, but does it also cause hypophosphatemia in the paradigmatic phosphate-wasting disorder X-linked hypophosphatemia (XLH)? It was previously reported that FGF23 can be cleaved by PHEX, the protease that is inactivated in XLH, suggesting that a failure to inactivate FGF23 could lead to its accumulation in XLH. This study reports that PHEX does not cleave FGF23. However, the level of FGF23 transcripts is markedly increased in bones ofHyp mice, an animal model of XLH. These data suggest that PHEX may work upstream of FGF23 to stimulate its secretion inHyp mice. The situation in XLH may be more complicated, because many patients have normal levels of FGF23. —GJS

◆ Qiu S, Rao DS, Palnitkar S, Parfitt AM. Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Miner Res. 2003 Sep;18(9):1657–63.

The osteocyte is getting some limelight. The authors suggest that deficits in osteocyte numbers may be a primary cause of bone fragility. Read this article, but refer also to the other work of these authors concerning superficial and deep osteocytes. What regulates the fate of osteoblasts as they either become lining cells or osteocytes or as they die? The latter is never a good career option.

◆ Rubin MA, Jasiuk I, Taylor J, Rubin J, Ganey T, Apkarian RP. TEM analysis of the nanostructure of normal and osteoporotic human trabecular bone. Bone. 2003 Sep;33(3):270–82.

The struggle for truth by reductionism continues. This paper demonstrates the plate-like crystal structure of the hydroxyapatite-like crystals in collagen. Dissecting out whether the source and progression of abnormalities in bone strength and microdamage is in collagen, crystal structure, mineral content, or some combination continues.

◆ Takuma A, Kaneda T, Sato T, Ninomiya S, Kumegawa M, Hakeda Y. Dexamethasone enhances osteoclast formation synergistically with transforming growth factor-b by stimulating the priming of osteoclast progenitors for differentiation into osteoclasts. J Biol Chem. 2003 Nov 7;278(45):44667–74.

Bone loss caused by corticosteroids is the result of a decline in bone formation. Increased bone resorption could contribute, as corticosteroids prolong the life span of existing osteoclasts. Another mechanism could be enhanced progenitor differentiation into cells of the osteoclast lineage.

◆ Yin JJ, Mohammad KS, Kakonen SM, Harris S, Wu-Wong JR, Wessale JL, Padley RJ, Garrett IR, Chirgwin JM, Guise TA. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10954–9.

Breast cancer is associated with both osteoblastic and osteolytic metastasis. This paper reports that several breast cancer cell lines that produce osteoblastic metastasis in a mouse model secrete endothelin-1. A specific antagonist of the endothelin-1 receptor ETA blocks the osteoblastic response to tumor cell-conditioned medium in organ culture, but an ETB antagonist does not. In a left ventricular model of bone metastasis in vivo, the ETA antagonist blocks both the development of both metastasis and the osteoblastic response. This is the best evidence to date for the mechanism of osteoblastic metastasis. —GJS

Physiology and metabolism

◆ Min JK, Kim YM, Kim YM, Kim EC, Gho YS, Kang IJ, Lee SY, Kong YY, Kwon YG. Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kB (RANK) in endothelial cells: Concomitant increase of angiogenic responses to RANK ligand. J Biol Chem. 2003 Oct 10;278(41):39548–57.

Recommended.

◆ Wu XB, Li Y, Schneider A, Yu W, Rajendren G, Iqbal J, Yamamoto M, Alam M, Brunet LJ, Blair HC, Zaidi M, Abe E. Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J Clin Invest. 2003 Sep;112(6):924–34.

Because noggin is a bone morphogenetic protein antagonist, it is arguably not surprising that osteoporosis is seen when the noggin gene is overexpressed in osteoblasts. It is interesting that the phenotype is not seen until eight months of age and that noggin levels increase with age in wild-type mice and are increased in SAM-P6 mice, a model of aging. Could expression of noggin be a determinant of age-dependent changes in osteoblast function? —GJS

Treatment and drug effects

◆ Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003 Sep 25;349(13):1216–26.

◆ Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ; PaTH Study Investigators. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003 Sep 25;349(13):1207–15.

◆ Khosla S. Parathyroid hormone plus alendronate—a combination that does not add up. N Engl J Med. 2003 Sep 25;349(13):1277–9.

Two papers report that overall, treatment of osteoporosis with the combination of parathyroid hormone (PTH) and alendronate is less effective than treatment with PTH alone. Not only does this discourage combination therapy, but it raises concerns about the efficacy of PTH in women who are switched from bisphosphonates (A recent abstract suggests that these concerns are valid [see J Bone Miner Res 18 (Suppl 2):S15]). —GJS

The two papers raise more questions than answers. Alendronate increases the mineral content of existing bone tissue, parathyroid hormone (PTH) increases bone tissue that is initially undermineralized then mineralized later, and both may alter marrow cellular composition. Thus, how should a higher or lower bone mineral density with combined therapy be interpreted? Static and dynamic histomorphometry, architecture, and anti-fracture efficacy is needed. Li et al. reported that rats given antiresorptives plus PTH do not increase breaking strength above that of PTH, but nor was there evidence of a reduction in breaking strength. If accepted on face value, the data suggest that rather than stimulating lining cells to become bone forming, the anabolic effect of combined therapy is dependent on bone resorption during remodeling. This might explain the loss of effect when treatment is stopped, the benefit of antiresorptives if given after PTH, and the lack of evidence for periosteal apposition in human studies.

◆ Iwaniec UT, Magee KA, Mitova-Caneva NG, Wronski TJ. Bone anabolic effects of subcutaneous treatment with basic fibroblast growth factor alone and in combination with estrogen in osteopenic ovariectomized rats. Bone. 2003 Sep;33(3):380–6.

There seems to be promising evidence to support the role of parenteral fibroblast growth factor as an anabolic agent. Antiresorptives may blunt the effect of parathyroid hormone (PTH). Several indirect studies suggest this possibility, but none of the studies have PTH alone arms, so I remain unconvinced. Nevertheless, anabolic agents are the way to go, and the present study and several other animal studies provide room for optimism. Studies in human subjects are anticipated with interest.

◆ Kanis JA, Johnell O, Black DM, Downs RW Jr, Sarkar S, Fuerst T, Secrest RJ, Pavo I. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone. 2003 Sep;33(3):293–300.

This is one of the few studies that suggests, in a reasonably convincing way, that antiresorptives are efficacious in reducing fracture rates in patients with osteopenia alone (i.e., in osteopenia patients without a fracture present). Data from other agents are less compelling — substantially less compelling.

Reviews, commentaries, and perspectives

◆ Barrett-Connor E. Clinical review 162: cardiovascular endocrinology 3: an epidemiologist looks at hormones and heart disease in women. J Clin Endocrinol Metab. 2003 Sep;88(9):4031–42.

Recommended.

◆ Heaney RP. How does bone support calcium homeostasis? Bone. 2003 Sep;33(3):264–8.

Recommended.

◆ Lee DK, Chang C. Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication. J Clin Endocrinol Metab. 2003 Sep;88(9):4043–54.

Recommended.

◆ Parfitt AM. Misconceptions (3): calcium leaves bone only by resorption and enters only by formation. Bone. 2003 Sep;33(3):259–63.