Saag KG. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357(20):2028-39.
This randomized study compared 18 months of either teriparatide or alendronate in 428 patients. The teriparatide was significantly better, both in increase of spine bone density and in reduction of spinal fractures, without serious adverse effects and with no difference in non-spine fractures.
Goh SK. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007;89(3):349-53.
Lenart BA Low energy femoral diaphyseal fractures associated with prolonged alendronate use: a case-control study. Abstracts, ASBMR meeting on Bone Remodeling, 2007, p.28.
The study by Goh found that 9 of 13 patients from their hospital who had non-traumatic subtrochanteric fractures were taking alendronate. These patients were younger than those with fractures who were on alendronate. The second study reviewed cases with low-energy femoral fractures from 2000-7 from the Hospital for Special Surgery, and compared the cases to controls who had a intertrochanteric or femoral neck fracture. The bisphosphonate use was 36.6% in the in subtrochanteric/shaft fracture cases, compared to 11% in hip fracture controls, odds ratio 4.68. The x-ray pattern showed cortical thickening in the alendronate cases.
Bauer DC. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 2006;21(2):292-9.
In women who had osteoporosis, those with bone formation rate in the lowest third (measured by P1NP) did not have any reduction in fracture rate when taking alendronate compared with placebo. Those in the upper third, however, had a significant reduction in fracture rates - enough to make the overall effect for the entire group signficant. In the near future we will first figure out what kind of osteoporosis a patient has, and then determine the best therapy.
Krajisnik T. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007;195(1):125-31.
Ben-Dov IZ. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007.
These studies show that the two important regulators of serum phosphate are related. Using cultured parathyroid cells, Krajisnik found that adding FGF23 inhibited the transcription and secretion of PTH. Also (unlike the effect of FGF23 in the kidney) the 1-alpha-hydroxylase was increased. It should be noted that klotho (necessary co-receptor for FGF23) is abundantly expressed in the parathyroid glands. Bon-Dov followed the klotho, and examined PTH secretion in transgenic mice over-expressing FGF23, and also found that FGF23 suppressed PTH gene expression and secretion. These studies demonstrate that the regulation of serum phosphate is complex!
Haney found that the risk of non-spine fractures was about doubled in the MrOs study of 5,995 older men, after adjusting for several other factors. Spangler reported an adjusted hazard ratio of 1.36 for spine fractures and 1.24 for non-spine, hip or wrist fractures in 93,676 women from the Women's Health Initiative.
You may have noticed that every year there are reports of this or that medication that can have negative effects on the bone. With the huge data-bases now available, another approach would be to look at all of the medications simultaneously to figure out which ones were associated with fractures. This method was presented in an abstract by Abrahamsen who coined the term prescriptiome to describe the entire complement of prescription drugs, using data about all the prescriptions used in Denmark. Drugs on the list included antiepileptics, opiods, dopaminergics, hormone antagonists, anti-depressants, insulin, loop diuretics, antipsychotics, analgesics, cardiac glycosides, and glucocorticoids.
Millan created a recombinant tissue-nonspecific alkaline phosphatase that was targeted to bone. They used this in mice with hypophosphatasia, and were able to reverse the phenotype for up to 2 months. When the therapy was discontinued, the animals developed osteomalacia and seizures. This approach may result in a treatment for children with hypophosphatasia.
Both Weinstein and Dempster reported finding giant osteoclasts in patients who had been treated with bisphosphonates. The photomicrographs were quite impressive. The cells were not resorbing bone, however.
Neutzsky-Wulff found osteoclasts from chloride channel -7 deficient mice were not able to resorb bone, but they were nevertheless able to stimulate osteoblasts.
Here is a list of novel therapies that have shown positive results in clinical trials with postmenopausal women:
Denosumab (Miller) N=229, 4 yr interim analysis, better BMD, more hospitalizations
Cathepsin K (Bone) N=399 for 1 year, better BMD
GLP-2 (Henriksen) N=160 for 6 months, better BMD
oral PTH-analogue (Hodsman) N=261 for 1 year, better BMD and increased markers
Anti-sclerostin antibody (Padhi) N=48, one dose increased formation markers
Activin receptor IIa+human IgG1 (Ruckle) N=48, one dose increased formation markers and decreased resorption markers.
and one study in 54 men given calcium-sensing receptor antagonist (Ethgen) found transient increases in the PTH.
Zhang studied the transcription factor Osterix, and found that it inhibits Wnt-signalling in osteoblasts, thus regulating osteoblast proliferation.
Gaur found that secreted-frizzled-related-protein knockout mice were able to heal fractures better than wild-type mice. The sFRP is a Wnt-signalling antagonist, suggesting that increased Wnt-signalling is helpful in healing fractures. This finding might lead to treatments that would accelerate fracture repair.
In addition, several abstracts about anti-sclerostin antibodies look promising.
Gagel found that deletion of the calcitonin gene caused profound cortical resorption in mice. This germ-line mutation is different from other studies of thyroidectomy.
Cauley measured 25(OH)vitamin D levels in 400 women from the Women's Health Initiative who had experienced a hip fracture, compared with matched controls. Those in the lowest quartile, with a value lower than 19 ng/ml, were 1.77 times more likely to have a fracture compared to those in the highest quartile. There was no difference in fracture risk among the 2nd to 4th quartiles, and the lowest risk was with levels between 24 and 28ng/ml.
Sato examined neuromedin U, a neuropeptide induced by leptin and found that it inhibited osteoblast proliferation and bone formation.
Dobnig found that teriparatide reduces bone microdamage accumulation in women treated with alendronate. They measured the crack density from biopsies in patients treated with teriparatide, with or without prior alendronate. Alendronate-treated biopsies showed increased number and length of cracks, but after teriparatide they were no different than non-alendronate treated patients.
Ichikawa S. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007;117(9):2684-91.
This is the first known human mutation of the klotho gene, and the patient had high phosphate, tumoral calcinosis, and high FGF23 levels. This demonstrates how necessary Klotho is for the function of FGF23, which is a hormone made in the bones that acts on the kidneys. She also had very high 1,25-vitamin D levels, which shows that phosphate controls vitamin D hydoxylation via FGF23 and not phosphate per se. Read more about klotho and review the function of FGF23 in the flash movie about phosphate transport in the section about osteomalacia.
Marini H. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med 2007;146(12):839-47.
This randomized trial found an improved bone density with genistein. There have been several other trials recently with mixed results, and none have been large enough to tell if there are any estrogen-like side effects if the doses are high enough to help the bones. I plan to review these studies soon.
Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(3):266-81.
A lot of new information is coming out about vitamin D. The effects on bone fractures, however, are not very impressive. The Vitamin D page has been updated.
Siminoski K. Recommendations for bone mineral density reporting in Canada: a shift to absolute fracture risk assessment. J Clin Densitom 2007;10(2):120-3.
Kanis JA. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007.
I have been using absolute fracture risks from the beginning, and finally other people are starting to embrace that idea. The Canadians have proposed a classification of fracture risk (low, moderate and high) instead of the normal/osteopenia/osteoporosis classification that is so confusing. Meanwhile the WHO has been doing meta-analyses and providing lots of data about the relative risks of clinical factors. These have all been incorporated into the revised Fracture Risk Calculator.
Other updates
There is a new section about discordance between spine and hip bone density measurements. Most of this is based on recent abstracts.
Update bisphosphonates
Eriksen EF. Remodeling and vascular spaces in bone. J Bone Miner Res 2007;22(1):1-6.
This concept was described by the authors several years ago, and Parfitt discussed the significance of this compartment in 2001. The current review induced me to modify the animations about bone remodeling.
Moe S. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;69(11):1945-53.
A new series of animations is on this revised page about Chronic Kidney Disease Mineral and Bone Disorder.
Feng JQ. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38(11):1310-5.
Dentin Matrix Protein is made in the osteocytes and it suppresses the levels of secreted FGF23 by osteoblasts. Mutations in DMP1 result in higher FGF23 levels, urine phosphate loss, and inappropriate 1,25-dihydroxyvitamin D levels. The osteocytes themselves are abnormal and are surrounded by unmineralized osteoid. This explains some rare cases of autosomal recessive hypophosphatemic rickets. Another report also found this mutation in different kindreds (Lorenz-Depiereux B).
The page about osteomalacia has been updated yet again.
Garman R. Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation. J Orthop Res 2007.
Mice subjected to tiny accelerations showed increased bone formation, even when there was no direct loading of the matrix. This was a small study involving only 8 vibrated mice, but the concept is important. The authors suggest that it may be possible to use this to develop treatments for patients confined to wheelchairs or bed rest.
Gilsanz V. Low-level, high-frequency mechanical signals enhance musculoskeletal development of young women with low BMD. J Bone Miner Res 2006;21(9):1464-74.
A device that looks like a bathroom scale which delivers low-magnitude vibrations was shown in this small study to increase bone density in young women who had fractures and a low bone density. The changes were detectable with QCT but not DEXA. There are currently several larger studies in different populations that can be found on the U.S. Clinical Trials website.
Johnell O. Whole lotta shakin' goin' on. J Bone Miner Res 2004;19(8):1205-7.
An editorial review of studies published a couple of years ago.
Be aware that not all vibrating platforms are the same; some may be harmful to the skeleton or the joints. Here is a link to a small video, which is admittedly an advertisement, but was shown at the recent ASBMR meetings. It makes the point and might make you smile: vibrations.
Hind K. Weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controlled trials. Bone 2007;40(1):14-27.
Meanwhile, "ordinary" weight bearing exercise may improve peak bone mass in children and adolescents. This is a new comprehensive review of the subject, and the authors found probable benefit but identify a need for better clinical studies to determine the best exercise program.
Yang YX. Long-term proton pump inhibitor therapy and risk of hip fracture. Jama 2006;296(24):2947-53.
This nested case-control analysis of the General Practice Research Database from UK found a 44% increased risk of hip fractures in patients who used proton pump inhibitors; the risk was even greater for those using higher doses and longer durations. The mechanism is not known but might relate to calcium absorption. Another recent study by Vestergaard P. also found an increased risk with these medications.
Black DM. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. Jama 2006;296(24):2927-38.
The rate of fractures was the same in the patients who took alendronate as in the ones who took placebo. These data were reported several years ago in abstract form and are not really new to readers of the bisphosphonate page.