Tian, E.(2003). The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349: 2483-94.
The investigators used gene array analysis to find which genes were expressed in myleoma cells that caused bone lytic lesions, and discovered that Dickkopf expression was significantly different in those with lytic lesions. This coincidence again shows the importance of the Wnt signalling pathway. Click to see a new section about Wnt-signalling and bone.
Jiang, Y.(2003). Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 18: 1932-41.
Bone biopsies from the large teriparatide study were analyzed by both histomorphometry and micro-CT scans. The mineralizing surface was slightly (not-significantly) lower after 19 months than at baseline. More details and an update of this treatment is found on the PTH page.
An article by Goss et al titled "A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer" will be published in the New England Journal of Medicine in November. It is now on-line, and has already been on the front page of the New York Times. Click here for a powerpoint presentation for a recent CME. It is a little blurry because I just saved the whole presentation for the web using the microsoft defaults, and I'll try to improve it when I finish writing a grant to study this more carefully.
The Effects of PTH, Alendronate Alone or in Combination on Bone Mass and Turnover: 12 Month Results of the PATH Trial. D. M. Black - - This was published the next week in the NEJM 238 women with osteoporosis randomized to PTH, alendronate or both showed higher BMD of spine with PTH (+6.2%) than alendronate (4.6%) and the combination was similar to PTH alone. QCT of spine showed PTH 23%, combination 11%, alendronate 7.6%. But at the hip, PTH was 0.8%, combination 1.8% and alendronate 2.0%
Parathyroid Hormone (1-34; Teriparitide) Enhances Experimental Fracture Healing Y. M. Alkhiary - - A study in rats showed that daily subcutaneous administration of low-dose teriparatide, PTH (1-34), enhances fracture healing by increasing BMD, BMC, and strength, and produces a sustained anabolic effect throughout the remodeling phase of fracture repair.
Response of Markers of Bone Turnover and Bone Density to Teriparatide in Postmenopausal Women Previously Treated with an Antiresorptive Drug B. Ettinger - - Women who had used alendronate or raloxifene (not randomized) for greater than 18 months were then given teriparatide for a year and markers of bone formation increased 139% after raloxifene but 118% after alendronate. Bone density of spine increased 7.7% after raloxifene and 2.5% after alendronate.
Daily versus Cyclic PTH Combined with Alendronate versus Alendronate Alone for Treatment of Osteoporosis F. Cosman - - In women who were already on alendronate >1 year, PTH increased markers and spine bone density. Giving PTH for 3 months and stopping 3 months in cycles gave final BMD result as daily, but pattern was more up and down.
Effects of Discontinuation of Teriparatide Treatment on Cortical Bone in Postmenopausal Women with Osteoporosis. C. E. Bogado - - 93 women who had discontinued teriparatide after 21 months showed no significant decrease at radius.
Changes in BMD at Different Skeletal Sites After Discontinuation of Treatment With rhPTH (1-34) in Postmenopausal Osteoporotic Women. J. R. Zanchetta - - same study as above, during followup spine decreased by 4%, hip by 1%, total body by 2%. However, bone density was still higher than baseline before PTH.
Differential Effects of Teriparatide and Alendronate on Markers of Bone Remodeling and Areal and Volumetric Bone Density in Women with Osteoporosis M. McClung - - Comparison of these showed bone mineralizing surfaces on biopsies was 8% after PTH and 0.2% after alendronate. With PTH, formation and resorption markers increased, whereas they decreased with alendronate. DEXA of spine was 4.7% with PTH and 3.2% with alendronate. QCT of spine was 14.6% with PTH vs 2.9% with alendronate. These were the 6 month data from the abstract.
Teriparatide (rhPTH [1-34]) Treatment Improves the Structure of the Proximal Femur in Women with Osteoporosis L. M. Semanick - - This was a more detailed analysis of the hip DEXA from the previously published study of teriparatide, using the Hip Structure Analysis program, showing improved buckling ratio with teriparatide.
Fibroblastic Growth Factors
A Missense Mutation in FGFR1 Causes a Novel Syndrome: Craniofacial Dysplasia with Hypophosphatemia. K. E. White - - this is the receptor for FGF, probably also for FGF-23, and mutation causes activation.
The Neutralization of FGF-23 Ameliorates Hypophosphatemia and Rickets in Hyp Mice Y. Aono - - A single injection of antibodies caused dose-dependent elevations of serum phosphate and 1,25D levels in Hyp mice. These findings were supported by evident accumulation of renal type IIa sodium phosphate co-transporter protein in renal brush border membrane, and also rickets improved
Evidence for a Physiological Role of FGF-23 in the Regulation of Renal Phosphate Reabsorption and Plasma Calcitriol in Healthy Humans S. L. Ferrari - - Diet which varied in phosphate caused changes in circulating FGF-23.
Increased Plasma Homocysteine Concentrations Are Strongly Associated with Increased Risk of Hip Fracture in Elderly Men and Women: The Framingham Study R. R. McLean
Risk Factors for Upper Limb Fracture in Children: A Population Based Case-Control Study D. Q. Ma - - factors were spine BMAD, television or computer watching, light physical activity, cola consumption. Hand fracures related to younger bone age than chronological age, high-risk sports. Obestiy was not associated with any fractures.
A Co-Twin Calcium Intervention Trial in Young Females: Effects Measured by Hip Structural Analysis J. D. Wark - - buckling ratio was better in those on calcium.
Maternal Vitamin D Status During Late Pregnancy and Accrual of Childhood Bone Mineral M. K. Javaid - - the children of mother with low vitamin D had lower body density nine years later.
Effects of Use and Discontinuation of Depot Medroxyprogesterone Acetate Injectable Contraception on Bone Density in Adolescents: Results from a Longitudinal Study D. Scholes - - we found significant bone loss in teenagers who used this method of contraception. There was at least partial recovery after discontinuation.
A Meta-analysis of Body Mass Index (BMI) as a Predictor of Fracture Risk C. E. D. De Laet - - Study of 190,000 person years, showed relative risk of hip fracture 4.18 with BMI of 15 vs 25, and 0.52 with BMI 40 vs 25. A woman with BMI of 20 was almost twice as likely to fracture her hip a woman with BMI of 25.
Increased Fracture Risk among Breast Cancer Survivors -Results from the Women's Health Initiative Z. Chen - - Overall 13.6% of breast cancer survivors had clinical fractures compared to 10.5% of reference group, hazard ratio was 1.3
Hip Fracture Risk is Increased in Men at Both High and Low Levels of Serum Vitamin A A. R. Opotowsky
The Use of BMD for Therapeutic Decision Making J. A. Kanis - - using clinical risk factors can predict who would have high and low risks, and then bone density is needed only in those with intermediate risk near the threshold values, in whom the bone density measurement would actually make a difference in the prediction of 10-year fracture risk.
Metabolic Bone Disease
Long-Term Control of Primary Hyperparathyroidism with Cinacalcet HCl (AMG 073) M. Peacock - - good results controlling calcium levels for 3 years.
Glitazones, the Anti-Diabetic PPAR-gamma Agonists, Pose a Significant Risk of Bone Loss; Differential Effects of Rosiglitazone and Netoglitazone. B. Lecka-Czernik - - in mice, roxiglitazone caused bone loss and may affect differetiation of stem cells towards adipocytes. Netoglitazone led to much smaller decreses in BMD.
COX-2 Inhibitors and Fracture Healing: Reversibility of Effects After Short Term Treatment L. C. Gerstenfeld - - in rats, the coxibs inhibited fracture healing, but after they were stopped the fractures did eventually heal and had normal torsional strength.
Delayed Fracture and Osteotomy Healing in Pediatric Osteogenesis Imperfecta Patients Receiving Pamidronate C. F. J. Munns - - When pamidronate had been started before surgery, 60% of osteotomies showed delayed healing compared with 16% not on pamidronate. Incomplete fracture healing in 27% on pamidronate vs 11% not on pamidronate.
WNT signalling pathway
Mechanical Loading Induces the Expression of Wnt Pathway Genes and Activation of the Wnt Pathway in Osteoblasts Enhances Loading Responses. J. Robinson
A Novel Association Between a Frizzled Related Protein Amino Acid Variant and Vertebral Fracture Risk in Older Women J. M. Zmuda
Whyte, M. P.(2003). Bisphosphonate-induced osteopetrosis. N Engl J Med 349: 457-63.
This fascinating case report of a child who was treated with high doses of pamidronate demonstrates the importance of bone resorption in modeling normal bone.
Manson, J. E.(2003). Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349: 523-34.
Several interesting new details were reported. In women who were within ten years of menopause, there were fewer myocardial infarctions in the estrogen-progesterone group than in the placebo group, especially if the women had hot flashes. Also, during year 6 there were fewer myocardial infarctions in the estrogen-progesterone group than in the placebo group. These data reinforce my recommendation that estrogen still can play a role in the prevention of osteoporosis when used in women who are recently postmenopausal.
Quarles, L. D.(2003). FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab 285: E1-9.
Jonsson, K. B.(2003). Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348: 1656-63.
The physiology of phosphate is still puzzling, but some of the factors are finally making sense. The osteomalacia page has been updated with animated diagrams of how this system seems to work.
Gonzalez, E. A.(2002). Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7. Kidney Int 61: 1322-31.
This study was published last year but I became aware of it at a recent workshop on renal osteodystrophy, which was organized by the National Kidney Foundation. The BMP-7, which is usually made in the kidney, can delay the maturation of osteoblasts, so the pre-osteoblasts accumulate and have been called "fibrosis". I just learned that the metabolic pathways of BMP-7 involve SMADs and the WNT signalling pathway, and I will post more about that as soon as I figure it out.
Renal phosphate transport is related to both hypercalciuria and kidney stones, osteoporosis, and osteomalacia. Check out the new section on hypercalciuria. The phosphate transport animations are found by clicking on the glomerulus.
Feskanich, D.(2002). Vitamin A intake and hip fractures among postmenopausal women. Jama 287: 47-54.
Promislow, J. H.(2002). Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res 17: 1349-58.
See a graph of these studies on the nutrition page.