What was new in 2006?

December 2006: Rosiglitazone causes increased fracture risk

Kahn SE. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355(23):2427-43.

In this clinical trial of 4360 patients with diabetes, the women randomized to rosiglitazone had a higher fracture rate (9.3%) than those treated with metformin (5.08%) or to glyburide (3.47%). This was an unexpected finding and there is just a short note added in proof at the end of the manuscript. Other recent studies have shown that this PPAR agonist is associated with greater bone loss ( Schwartz AV ) and with differentiation of marrow precusor cells into adipocytes instead of osteoblasts ( Crossno JT, Jr., Ali AA). Another related report from the Women's Health Initiative has shown that patients with type 2 diabetes already have an increased risk of fracture at multiple sites, despite their obesity and higher bone density. The adjusted risks were 20% higher for any fracture and 82% higher at the hip, pelvis and upper leg, and adjustment included fall history ( Bonds DE).

October 2006: Some ASBMR abstracts

ASBMR 2006 search engine

Effect of Once-Yearly Infusion of Zoledronic Acid 5 mg on Spine and Hip Fracture Reduction in Postmenopausal Women with Osteoporosis: The HORIZON Pivotal Fracture Trial -- D. M. Black A 3 yr clinical trial, N=7736 from 240 clinical centers. Women aged 65-89 with T-score less than -2.5 or fracutre and less than -1.5. They were allowed to take these other osteoporosis medications: calcitonin, SERM, hormones, tibolone. There were 70% fewer vertebral, 40% fewer hip and 25% fewer non-vertebral fractures. After the infusion 15% had pyrexia, 8% had myalgias. Only a small number had increased creatinine, and there was no cummulative impact on the kidney or jaw osteonecrosis. Calcium was transiently decreased. Atrial fibrillation occured in 1.2% compared to 0.4% in the placebo group. 93 bone biopsies all showed some tetracycline labels. Bone markers showed decreased CTX and BSAP and P1NP (to mid premenopausal range).

Femoral Bone Strength after Two Years of Treatment of PTH, Alendronate, or PTH + Alendronate: Finite Element Analysis of the PaTH Study -- T. M. Keaveny This was the most thought-provoking abstract because it re-introduces the notion of a fracture threshold. Theoretically, only patients who cross the threshold will show a treatment-related effect of a therapy on hip fracture rates. Those above the threshold before and after treatment would not have fractured anyway, and those below this threshold will fracture despite treatment if they should fall.

The Association between Bone Mass and Fractures in Childhood: A Prospective Cohort Study -- E. M. Clark These investigators measured bone density in 7333 ten-year old children, and aften 2 years there was an 89% increase in fracture risk for each SD decrease in bone density.

Fracture Risk and Site-Discordance: The Total Hip Dominates Other Sites -- W. D. Leslie Bone density was measured in 16,505 postmenopausal women, and the rate of fractures over the next 3 years was best predicted by BMD of the total hip. Adding spine or using femoral neck did not help predict fractures.

Microcrack Frequency and Bone Turnover in Osteoporotic Women on Long-term Bisphosphonates : a Bone Biopsy Study -- R. Chapurlat They did not find any micro-cracks, but there was no tetracycline uptake in a third of the patients.

Effect of One Year Treatment with the Cathepsin-K Inhibitor, Balicatib, on Bone Mineral Density (BMD) in Postmenopausal Women with Osteopenia/Osteoporosis -- S. Adami In this clinical dose-finding study of 675 women, there was an increase in bone density after one year. Markers of bone resorption decreased but bone formation markers did not. At higher doses there were some dermatological side effects with scleredema-like changes.

Mechanical Loading Reduces Osteocyte Expression of Sclerostin Protein. -- A. G. Robling In mice whose limb was mechanically loaded, the expression of sclerosin in the osteocytes was reduced

Administration of Sclerostin Monoclonal Antibodies to Female Cynomolgus Monkeys Results in Increased Bone Formation, Bone Mineral Density and Bone Strength -- M. Ominsky The title tells the story

Anti-Catabolic Therapy Exacerbates Osteomyelitis without Altering Humoral Immunity. -- D. Li In mice, a transtibial pin was contaminated with staph, and osteomyelitis developed in those treated with either alendronate or OPG. The mechanism did not involve IgG production.

Long-Term Control of Primary Hyperparathyroidism with Cinacalcet. -- M. Peacock After 5 years in 45 patients the PTH was still controlled and calcium remained normal, without serious side effects

PTH Once Weekly Increases BMD and Is Mildly Anabolic in Postmenopausal Osteopenic Women: Results from the PTH Once Weekly Research (POWR) Study. -- D. M. Black This was a pilot study of 50 women, randomized to no treatment vs PTH daily for one month and then weekly for 11 months. There was mild increase in bone density, 2.1% higher than control at the spine and no difference at the hip

Fibroblast Growth Factor-23 (FGF-23) in Children with Chronic Kidney Disease. -- H. E. Price The levels of FGF-23 increased as GRF decreased, but there were no correlations with serum phosphate or PTH.

Anabolic Responses of Bone to Parathyroid Hormone Are Maintained in Mice with Deficient Osteoclast Formation and Activity. -- J. A. Lorenzo PTH can have anabolic actions without needing to first have bone resorption or even osteoclasts.

August 2006: Claudin-16 in the tight junction

Kausalya PJ. Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16. J Clin Invest 2006;116(4):878-91.

This protein, formerly known as paracellin-1, is located in the tight junctions of the thick ascending limb of the nephron. It selectively increases permeability of sodium, which sets up a transepithelial potential difference that drives reabsorption of magnesium and calcium. Patients with mutations in this gene develop hypomagnesemia, hypercalciuria and renal failure. This paper explores how specific mutations lead to abnormalities. Sometimes the protein does not fold properly, and certain drugs ("pharmacological chaperones") can rescue the protein.

Other related papers have been recently published, including:

Hou J. Paracellin-1 and the modulation of ion selectivity of tight junctions. J Cell Sci 2005;118(Pt 21):5109-18.

Weber S. Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 2001;12(9):1872-81.

Simon DB. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999;285(5424):103-6.

See animated cartoons of calcium transport in the kidney on this page about hypercalciuria.

July 2006: Imatinib causes hypophosphatemia

Berman E. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354(19):2006-13.

Imatinib, a drug used to treat certain cancers (CML or gastrointestinal stromal tumors) causes hypophosphatemia, renal phosphate wasting, and biochemical evidence of low bone turnover. The mechanisms are not clear - - - the authors suggested it was due to suppression of the RANK-L signalling, but other drugs which block bone turnover, or which directly block RANK-L signalling do not cause low phosphate. I wonder if this drug may interact with some of the newly discovered Klotho or other phosphatonins. The page about osteomalacia has been updated.

May 2006: Updates about raloxifene

Last month the results of two large trials were announced. These have not yet been presented at meetings or published in peer-reviewed papers. The STAR trial was sponsored by the NIH and enrolled 19,747 women with high risk of getting breast cancer. They were randomly assigned to raloxifene 60mg/day or tamoxifene 20mg/day for 5 years. The groups had similar rates of invasive breast cancer, about half of the predicted rate. Raloxifene had fewer side effects and fewer cases of uterine cancer. Tamoxifene was better at preventing non-invasive breast cancer. Overall, the benefit profile favored raloxifene.

The RUTH study was conducted by Lilly, who announced the results. This was a multi-center, international study of over 10,000 women with heart disease or high risk, who were given placebo or raloxifene for up to 7 years with primary endpoint of cardiovascular disease. There was no protection from heart disease or stroke. There were more cases of fatal stroke but that was an unusual event. There were fewer cases of invasive breast cancer. No mention was made of fractures, and details will have to wait for publication. Read more about raloxifene on this web site.

April 2006: Rank-ligand inhibition - possible new therapy for osteoporosis

McClung MR. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354(8):821-31.

This was a phase 2 study of an antibody to RANK-L. The bone density increased, and markers of bone resorption and bone formation decreased. This is another anti-resorbing medication with a very different mechanism of action. More information is on this new page. Also, the page about experimental therapies. has been updated.

March 2006: Klotho: the fountain of youth?

Kurosu H. Regulation of fibroblast growth factor-23 signaling by Klotho. J Biol Chem 2006.

Razzaque MS. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. Faseb J 2006.

Here are two of the most recent in a series of fascinating papers about klotho, a gene which prevents aging in mice, and is related to FGF23, calcifications, vitamin D, phosphate homeostasis, and osteoporosis. There are some graphic notes on this new page: klotho.

February 2006: Calcium plus vitamin D: Modest effects

Jackson RD. Calcium plus Vitamin D Supplementation and the Risk of Fractures. New Engl J Med 2006:354:669-83.

This study of 36,282 women from the Women's Health Initiative showed no significant reduction in fractures in those assigned to take supplements of calcium and vitamin D, but there was an increased risk of kidney stones. This news is not all that surprising because some previous studies did not show benefits of excess calcium in ordinary women. The findings of kidney stones suggest that calcium intake should not be greater than 1500mg/day. See page about calcium.

January 2006: Osteonecrosis of the jaw

Ruggiero SL. Practical guidelines for the prevention, diagnosis and treatment of osteonecrosis of the jaw in patients with cancer. J Oncology Practice 2006;2(1):7-14.

Marx RE. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63(11):1567-75.

Bamias A. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23(34):8580-7.

This complication of bisphosphonate therapy has been recently recognized. A new page about jaw osteonecrosis has been added to this site.

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