Takeda, S.(2002). Leptin regulates bone formation via the sympathetic nervous system. Cell 111: 305-17.
There is still lots of research about leptin. This one is particularly interesting because it involves the sympathetic nervous system. A few more new references about leptin are also listed.
Parathyroid hormone 1-34 has been approved by the FDA and there is a new page, new movies, new references.
These are all real cases. Test your BMD reading skills!
Cummings, S. R. Clinical use of bone densitometry: scientific review. Jama 288: 1889-97.
Here is an update of data from the Study of Osteoporotic Fractures, with 5 years of data. The fracture results are (finally) reported as absolute risks, and they have been used to update my Fracture Risk Calculator
Morabito, N. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res 17: 1904-12.
This was a randomized blinded trial in 90 women aged 47-57, comparing estradiol, genistein, and placebo. The estradiol and genistein both decreased pyridinium and improved bone density. The interesting finding was that genistein also increased the bone specific alkaline phosphatase and osteocalcin, whereas estradiol decreased those values.
Here is a list of the abstracts that I thought were the most interesting this year. I will be working on putting links to relevant pages in this website.
Frizzled and Wnt-signaling
F. Bex. Skeletal Phenotype of Mice Expressing the Human High Bone Mass Gene. In transgenic mice with the mutation in the LRP5 gene, there was an increase (125-232%) in trabecular bone volume, no differences in osteoclast number, 33% increase in actively mineralizing bone surface and a significant reduction in the number of TUNEL positive osteoblasts. The increased bone density in the transgenics was associated with significant increases in vertebral compressive and femoral bending strength
P. Bodine. Targeted Disruption of Secreted Frizzled-Related Protein (SFRP)-1 in Mice Leads to Decreased Osteoblast and Osteocyte Apoptosis and Increased Trabecular Bone Formation. SFRP-1 is a secreted Wnt antagonist. In order to determine if SFRP-1 affects osteoblast function in vivo, we generated a knockout (-/-) mouse. SFRP-1 is a negative regulator of osteoblast and osteocyte survival, osteoblast differentiation and bone formation in mice. Moreover, deletion of SFRP-1 results in a temporal delay of age-related trabecular bone loss.
R. F. Klein. Frzb1, an Inhibitor of Wnt Signaling, is Over-expressed in Chondrocytes from Low Bone Mass Mice. To explore the genetic architecture of peak BMD, reciprocal congenic strains were developed. QTL regions from Chr 1, 2, 4, & 11, defined by chromosomal molecular markers, were transferred from B6 to D2 and vice versa by 10 cycles of backcrossing. Frzb1 encodes a secreted antagonist of Wnt signaling. The recent identification of mutations in low-density lipoprotein receptor-related protein 5 (LRP5) in humans and now Frzb1 in mice suggests that the Wnt signaling pathway likely plays an important, and previously unrecognized, role in the attainment of peak BMD
S. Roman Roman. Wnt-mediated Signaling via LRP5 and Beta-catenin Induce Osteoblast Differentiation and Mediates the Effects of BMP2. In conclusion our data demonstrate a crucial role of Wnt-mediated signaling via LRP5 in osteoblast function.
J. S. Finkelstein. Effects of Parathyroid Hormone, Alendronate, or Both on Bone Density in Osteoporotic Men. These data suggest that combining PTH and ALN is superior to PTH alone for total body BMD but that ALN may diminish the anabolic effect of PTH on spine BMD
R. Neer. Effects of Parathyroid Hormone, Alendronate, or Both on Bone Density in Osteoporotic Postmenopausal Women. Adding ALN reduced the PTH-induced increase in serum alkaline phosphatase and did not alter PTH's effects on vertebral BMD. The superior changes in total hip, radius diaphysis, and total body BMD suggest that ALN prevents PTH-induced losses of cortical bone mineral.
Y. Jiang. Improved 3-Dimensional Microstructure of Cancellous and Cortical Bone in a Multicenter, Double-Blind, Randomized and Placebo Controlled Study of Teriparatide [rhPTH(1-34)]. 3-dimensional micro-computed tomography (3DµCT), paired biopsies were obtained from women in the placebo group (n=19) and the combined teriparatide treated group [20 µg (n=18) and 40 µg (n=14)] at baseline and after 18 ± 5 months (mean ± SD).
RANK-RANK L-OPG (including Mice in Space!)
G. Eghbali-Fatourechi. Role of RANK Ligand (RANKL) in Mediating Increased Bone Resorption in Early Postmenopausal Women They aspirated bone marrow from 12 premenopausal women, 11 early postmenopausal women, and 13 postmenopausal women receiving long-term estrogen therapy (Postmps + E). Upregulation of RANKL on bone marrow cells is a major determinant of increased bone resorption during E-deficiency
P. J. Kostenuik. OPG Prevents Relative Osteopenia and Deficits in Skeletal Strength in Mice During a 12 Day Spaceflight 10 week old female mice (n=12/group) were injected once with OPG (20 mg/kg) or with vehicle (VEH), 24 h prior to launch. Ground control mice were maintained under environmental conditions that mimicked those in the shuttle middeck. A single pre-flight treatment with OPG effectively prevented the deleterious effects of SF on mouse bone.
B. Chong. Mutations in the Gene Encoding Osteoprotegerin Cause Idiopathic Hyperphosphatasia Mutations were detected in two of the four families reporting parental consanguinity. No mutations in TNFRSF11B or its promoter region were identified in the six other families
R. Emkey. Ten-Year Efficacy and Safety of Alendronate in the Treatment of Osteoporosis in Postmenopausal Women. In a study of 994 postmenopausal osteoporotic women. We reported 7 yr results from 350 women who, after 5 years of continuous ALN treatment, participated in a double-blind 2 yr extension (Yrs 6-7), and now report the results for 247 women who entered an additional 3 yr extension. Cumulative 10 yr spine BMD increases were 13.7 % with ALN 10 mg and 9.8 % with 5 mg. At the hip and total body, prior increases in BMD were maintained during Yrs 8-10. Non-vertebral fractures during Yrs 8-10 were 8.1, 11.5, and 12.0 % in the ALN 10 mg, 5 mg and A-PBO groups. The 3 yr incidences in the original cohort during Yrs 1-3 were 8.5 % (pooled ALN) and 10.7 % (placebo). In response to my question, they said the vertebral radiographs had not yet been measured.
E. J. Smith. Removal of Unremodelled Growth Plate in the Metaphysis after Bolus Zoledronic Acid in Growing Rabbits Tibial length was 3-7% shorter. This study shows that zoledronic acid causes transient retention of growth plate remnants in the metaphysis, in association with transient inhibition of growth.
Phosphatonin and FGF-23
K. B. Jonsson. FGF-23 Is a Circulating Factor that Is Elevated in Oncogenic Osteomalacia and X-linked Hypophosphatemic Rickets Healthy individuals revealed FGF-23 concentrations of 55.6±50.6 RU/mL (mean±SD). Four OOM patients had concentrations ranging from 426.1 to 7970.0 RU/mL, which returned to normal after successful surgical tumor removal. The investigators suggest that PHEX may degrade FGF-23.
Y. Yamazaki. FGF-23 Protein is Present in Normal Plasma and Is Increased in Patients with Tumor-Induced Osteomalacia we demonstrated the presence of FGF-23 in circulation of healthy subjects and the elevation of FGF-23 in a patient with TIO.
H. C. Allen. Endocrine Response to Escalating-Dose Phosphate Supplementation in Men: Is FGF-23 Phosphatonin? Twelve healthy men were studied for 5 weeks. Renal phosphate excretion increased with escalating phosphate intake. Fasting FGF-23 increased significantly.
Some practical findings relating to osteoporosis management
M. Sinaki. Reducing Risk of Vertebral Fracture Through Specific Back Exercises: A Long Term Follow-up Fifty women, aged 58 to 75 years, who had completed a 2-year, randomized controlled trial 10 years earlier. Physical activity was not significantly different between the 2 groups at baseline but at 10 years still significantly higher in the treatment group. The difference in BMD, which was not significant between the 2 groups at baseline and 2-year follow-up, was significant at 10-year follow-up. Also there were fewer vertebral bodies with fractures.
R. D. Jackson .The Impact of Magnesium Intake on Fractures: Results from the Women's Health Initiative Observational Study We examined the relationship between Mg intake and hip, wrist/lower arm and other clinical fractures in 89,717 postmenopausal women age 50-79.The bone density was higher in those with highest magnesium intake, but the fracture rate was higher. These findings indicate that high Mg intake does not confer a protective effect against fracture and in fact, may increase the risk of wrist/lower arm fractures.
N. M. van Schoor. Effectiveness of External Hip Protectors in Preventing Hip Fractures: A Randomized Clinical Trial Elderly persons with high risk were ssigned to the hip protector group (n=276) or control group (n=285); the compliance was 61% after 12 months. By intention to treat, 18 persons from the hip protector group fractured a hip during the study period versus 20 persons from the control group. Only 4 persons from the hip protector group were actually wearing the hip protector while fracturing a hip.
NIH news release
The Women's Health Initiative, which was due to end in 2005, was terminated today because the risk of breast cancer was higher than the safety limit. The study lasted an average of 5 years. The part of the study for women taking estrogen alone was not stopped, and in that study the risk of breast cancer is not increased. This suggests that most healthy postmenopausal women should not take long-term progestin plus estrogen. The contribution of progestins to this picture is not yet certain, but it seems that they increase the risk of breast cancer compared to estrogen alone, as suggested by other previous studies. Heart disease risk was also increased. Go to page about estrogen for more details.
Meunier, P. J.(2002). Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis--a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 87: 2060-6.
This study in 353 women with osteoporosis showed a reduction in vertebral fracture rate and increased bone density. The agent appears to be anabolic. There have been several smaller studies in the past with the agent, which will probably be getting more attention in the future.
Boyden LM. (2002). High Bone Density Due to a Mutation in LDL-Receptor-Related Protein 5. N Engl J Med 346:1513-21.
This is a report of another family with a mutation in the LRP-5 gene, which caused high bone density as well as thick mandible. The authors further demonstrated that the mutation led to resistance to Dickkopf (Dkk), an inhibitor of the Wnt-signalling pathway. The un-inhibited pathway resulted in increased levels of fibronectin. The TGF-beta and osteocalcin were also elevated in affected family members. I have a few notes about the Wnt signalling pathway which followed an earlier report of another family who had mutations in the same gene, at the same place.
Ott, S. M.(2002). Bone histomorphometric and biochemical marker results of a 2-year placebo-controlled trial of raloxifene in postmenopausal women. J Bone Miner Res 17: 341-8.
Finally, my paper is in print. See the animation, which is more fun than wading through the tables of data.
To convert T-scores to Z-scores, or calculate standardized BMD, fracture risk, percentile, percent from average for a DEXA measurement, check out the new Fracture Risk Calculator
Reseland, J. E.(2001). Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res 16: 1426-33.
Holloway, W. R.(2002). Leptin inhibits osteoclast generation. J Bone Miner Res 17: 200-9.
Whereas some older studies found that leptin inhibited bone formation, these show an enhanced mineralization. Also, leptin may act by increased osteoprotegerin! See the new web page about leptins.