Promising results using antibody to Rank-Ligand
AMG 162 Increases Bone Mineral Density (BMD) Within 1 Month in
Postmenopausal Women With Low BMD. M. R. McClung, E. M. Lewiecki, M. A. Bolognese , G. Woodson , A. Moffett, M. Peacock , P. D. Miller , S. Lederman , C. H. Chesnut , R. Murphy , D. L. Holloway, P. J. Bekker.
Women were randomly studied for one year, given various doses and regimens of this injection every 3 months or 6 months, and bone density increase was better than with alendronate at cortical sites. No serious side effects were seen in the studies involving 411 women.
Similar fracture rates with or without alendronate after 5 years
A 5 Year Randomized Trial of the Long-term Efficacy and Safety of Alendronate:
the FIT long-term extension (FLEX) D. Black, A. Schwartz, K. Ensrud, A. Rybak-Feiglin , J. Gupta, A. Lombardi, R. Wallace , S. Levis, S.
Quandt, S. Satterfield , J. Cauley, S. Cummings.
About 30% of the women from the FIT study who had been taking alendronate for 5 years participated in an extention and were randomly treated with 5 more years of alendronate or a placebo. The fracture rates for vertebral morphometric (measured) fractures were not different, relative risk 0.87, and the overall non-spine fractures were almost identical, relative risk 1.0. The bone density did decrease after stopping the alendronate, but the continued increase in DEXA scores did not result in fewer fractures.
What to do after stopping PTH
The Effect of 1 year of Alendronate Following 1 year of PTH 1-84: Second Year
Results from the PTH and Alendronate (PaTH) Trial. D. M. Black, C. J. Rosen, L. Palermo, T. Hue, K. E. Ensrud, S. L. Greenspan, T. F. Lang, J. A. McGowan, J. P.
Bilezikian.
Subjects from the PATH trial who took PTH were randomly given alendronate or placebo after the year of PTH therapy. Those on placebo lost bone density, whereas those on alendronate gained more bone density.
"These data suggest that BMD gains after 1
year of PTH(1-84) are quickly lost in the next year if PTH is not followed by an antiresorptive
agent."
More studies involving the Wnt-signalling pathway
Inhibition of GSK-3Beta, by lithium chloride reverses the osteoporotic
phenotype displayed by Lrp5, deficient mice and increases bone density in intact C57Bl6 and in Osteopenic SAMP6, mice. P. Clement-Lacroix, M. Ai , R. Chiusaroli , F. Morvan , S. Roman Roman, B. Vayssiere , C. Belleville , M. Warman , R. Baron, G. Rawadi.
"These
data strongly suggest that the low bone mass in Lrp5-/- mice results from a defective
canonical Wnt signalling. Furthermore, LiCl is able to significantly increase bone formation
parameters in intact C57Bl6 and in osteopenic SAMP6 mice."
An Orally Bioavailable GSK3 Alpha-beta Dual Inhibitor Increases Markers of Cellular
Differentiation and Bone Mass In Vitro In Vivo. N. H. Kulkarni, M. Liu, D. L. Halladay, C. A. Frolik, T. A. Engler, L. M. Helvering , T. Wei , A.
Kriauciunas, T. J. Martin, M. Sato, H. U. Bryant, J. E. Onyia, Y. L. Ma.
". . . increased bone mass in ovariectomized rats, induced osteoblast differentiation in vitro and
increased markers of bone formation both in vitro and in vivo. These observations are consistent
with the pronounced role played by the canonical Wnt pathway in osteogenesis."
Role of Dickkopf (Dkk) in Myeloma Bone Disease and
Modulation by the Proteasome Inhibitor Velcade. B. O. Oyajobi, I. R. Garrett, A. Gupta , M. Banerjee , X. Esparza , A. Flores , J. Sterling, G. Rossini , M.
Zhao, G. R. Mundy.
"Taken together, our data indicate that the strikingly beneficial
effects of proteasome inhibition now being reported in myeloma patients likely results
from its multiple effects on inducing tumor cell death whilst concomitantly promoting
osteogenesis by reducing Dkk-1 expression and inhibiting osteoclastic bone resorption."
Studies of bone disease in men
'Viva le Difference!' Bone Mass and Fractures in Men versus Women from
SOF (Study of Osteoporotic Fractures) and MrOS (Osteoporotic Fractures
in Men). S. R. Cummings, P. M. Cawthon, J. A. Cauley, K. E. Ensrud, D. C.
Bauer, H. A. Fink, D. M. Black, E. S. Orwoll.
The differences between men and women were complex. At high bone density, men and women with the same bone density (in g/cm2) had the same risk of fractures, but at low bone densities women had a higher risk than men. When using T-scores, men with "normal" DEXA had fracture incidence of 0.9%/yr and women 2.7%/year. With "osteopenia" men had 1.7%/yr incidence and women had 4.2%/yr incidence. So the definitions for women can't easily be transfered to men. Some of the differences were attenuated by adjustment for mineral content.
Quantitative Ultrasound Predicts Hip and Non-spine Fracture in Men:
the MrOS Study. D. C. Bauer, J. A. Cauley, K. E. Ensrud, S. Ewing , E. S. Orwoll.
"We conclude that QUS measurements predict the risk of hip and other non-spine fracture in
older men, and do so nearly as well as hip BMD measurements."
SSRI Use Is Associated with Lower BMD Among Men . E. M. Haney, B. K. S. Chan, L. Lambert, J. Cauley, K. Ensrud, E. Orwoll, M. Bliziotes.
Adrenergic receptors - mixed results
Last year studies suggested that leptin acted via the sympathetic nervous system to decrease bone formation, and a recently published epidemiological study found lower fracture rates in patients taking beta-blockers for hypertension.
Deletion of the Beta-2 Adrenergic Receptor Prevents Bone Loss Induced by Isoproterenol in Mice. H. Z. Ke G. XU A. L. Brault H. Qi D. T. Crawford H. A. Simmons M. Li T. A. Brown.
There were no differences in bone mass between wild-type and knock-out mice, but after isoproterenol the wild-type mice lost bone density. This was not, however, caused by inhibited bone formation, but rather by increased bone resorption and increased bone formation.
Beta1-Beta2-Adrenergic Receptor KO Mice Have Decreased Total Body and Cortical Bone Mass Despite Increased Trabecular Number. D. D. Pierroz, P. Muzzin , V. Glatt , M. L. Bouxsein, R. Rizzoli, S. L. Ferrari.
Beta-Adrenergic Receptor KO Mice Have Increased Bone Mass and Strength But Are Not Protected from Ovariectomy-Induced Bone Loss. H. Dhillon , V. Glatt , S. L. Ferrari, M. L. Bouxsein.
Too much vitamin D can increase fractures
Effect of Annual Intramuscular Vitamin D Supplementation on
Fracture Risk in Community-Living Older People: The Wessex Fracture Prevention Trial.
F. H. Anderson, H. E. Smith , H. M. Raphael , S. R. Crozier , C. Cooper.
9,440 elderly men and women were randomly given an injection of vitamin D or placebo along with their annual flu shot. The relative hazard in the vitamin D group was 1.48 for a hip fracture. "We conclude that an annual intramuscular injection of 300,000 IU vitamin D is not effective
in preventing hip and other non-spine fractures among elderly men and women".
Another potential new therapy
Sclerostin Antagonism in Adult Rodents, via Monoclonal Antibody
Mediated Blockade, Increases Bone Mineral Density and Implicates Sclerostin as a Key Regulator
of Bone Mass During Adulthood. K. Warmington , S. Morony, I. Sarosi , J. Gong , P. Stephens , D. G. Winkler, M. K. Sutherland, J. A. Latham, H.
Kirby, A. Moore, M. Robinson, P. J. Kostenuik, S. Simonet, D. L. Lacey, C. Paszty.
Another important signalling pathway in osteoblast differentiation
Osteopenia and Reduced Bone Formation Due to a Mutation in the
Indian Hedgehog (IHH) Gene. L. Gennari, D. Merlotti, N. Giordano , V. De Paola , A. Calabr , G. Martini, A. Renieri, R. Nuti.
"In summary we report the first evidence that
mutations in the IHH gene in man, causing BDA-1, may be associated with low bone formation,
osteopenia and increased fracture risk."
Sequential Roles of Hedgehog and Wnt Signaling in Osteoblast
Development. F. Long, H. Hu.
"These data support a
model in which Hh signaling directs osteoprogenitors along the osteoblast lineage and subsequently
induces either directly or indirectly expression of Wnts, which further promotes
osteoblast development."
ASBMR BONE CURRICULUM
I have been working on the web page for the ASBMR Bone Curriculum, which is why these updates are behind schedule. Click on the link to see the new pages!
Schlienger, R. G.(2004). Use of beta-blockers and risk of fractures. Jama 292: 1326-32.
The case-control study from the UK General Practice Research Database of 120,819 controls and 30,601 fracture cases found the odds ratio of fractures in patients who used beta-blockers was 0.77, and for thiazides it was 0.80. The combination odds ratio was 0.71.
Fratzl-Zelman, N.(2004). Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab 89: 1538-47.
This is a detailed report bone biopsies from patients with this rare disease caused by cathepsin K mutations. Patients have high bone density but fragile bones and poor bone quality.
Block, G. A.(2004). Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350: 1516-25.
Cunningham, J.(2004). Osteoporosis in chronic kidney disease. Am J Kidney Dis 43: 566-71.
Cinacalcet is a calcimimetic that activates the calcium receptor and reduces PTH secretion. In this placebo-controlled multi-center trial, PTH, serum phosphate and serum calcium were signficantly decreased. This drug has just been approved by the FDA and has potential for medical therapy of hyperparathyroidism. Another recent article is a review of an international panel who discussed osteoporosis in patients with kidney disease. There has not been much research about therapy in these patients who have an increased fracture risk. More about renal osteodystrophy is on this recently updated page.
Anderson, G. L.(2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Jama 291: 1701-12.
We have been waiting for these results. The effects of estrogen on fracture reduction continue to be very significant - those who took estrogen had about half as many fractures as those on placebo. In younger women (50-59 yrs) the overall effect of estrogen was slightly beneficial but this was not statistically significant. The risk of breast cancer was not reduced; in fact, in this study the women who took estrogen had fewer breast cancers. They did have more strokes, which caused the NIH to prematurely stop the study, but the absolute risk of stroke was small. Overall the estrogen and placebo group had similar mortality and quality of life. See the results graphed on the estrogen page.
Rubin, C.(2004). Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res 19: 343-51. Epub 2003 Dec 22.
Ward, K.(2004). Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res 19: 360-9. Epub 2004 Jan 27.
These are reports of a new vibrating platform that appears to be anabolic for the cancellous bone. This new approach to treating osteoporosis is exciting and if future larger trials continue to show benefit, I am going to get one of those platforms.
Shane, E.(2004). Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 350: 767-76.
Alendronate and calcitriol had similar beneficial effects on bone density in this high-risk population. The transplantation pages will soon be updated with this data.