What was new in 2008?

December 2008: Rickets from too much Klotho

Brownstein CA. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A 2008;105(9):3455-60.

First we had a case report of a patient with a klotho mutation that caused low levels, and the patient had tumoral calcinosis. This is the first case of a patient with high klotho levels, caused by a translocation. Unlike the mice which over-express klotho and are healthy and long-lived, this patient had hypophosphatemic rickets. At first she seemed to have regular x-linked hypophoshpatemia, but after gene testing showed no mutations, further studies disclosed the real cause. Interestingly, the FGF23 level is elevated with both kinds of klotho mutations. This is yet another cause of osteomalacia so the page was updated again.

November 2008: Serotonin and SSRIs

Yadav VK. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008;135(5):825-37.

This is a very complex paper describing a series of studies in genetically altered mice. The mice with knock-out of LRP5 in the gut cells (but NOT in the osteoblast cells) had low bone density. They also had increased blood serotonin levels, and the disease was treated with a low tryptophan diet (which lowers serotonin). Recall that LRP5 is a co-receptor for the wnt-signalling pathway. LRP5 is inhibited by sclerostin, and other studies have shown that the osteocyte sclerostin secretion regulates bone formation in response to mechanical loading. Signalling through LRP5, however, is not the only way to activate the pathway. This paper suggest that another pathway, involving serotonin and a serotonin receptor (Htr1b) can also inhibit osteoblasts. Patients with the very rare disease "osteoporosis pseudoglioma" have elevated serotonin levels.

This study does not explain the role of serotonin in normal physiology and does not mention the role of osteocytes, nor the findings of some other investigators who do find that wnt-signalling in osteoblasts causes high bone density. The authors, in their discussion, state that their findings do not explain why patients taking medicines for depression called "selective serotonin reuptake inhibitors" develop osteoporosis. Nevertheless, it seems that there may be a connection between these mouse studies and the clinical findings in patients taking these anti-depressant medications. There have been several recent studies which are listed on the new page about SSRIs. These reports from large cohorts have found about 1.5 to 2 times the risk for fractures, even after adjusting for depression. Clearly this is an area that needs further study.

October 2008: Vitamin D and mortality

Melamed ML. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168(15):1629-37.

This large followup study from the NHANES population showed that low levels of vitamin D were associated with higher mortality. Of interest, high levels were also associated with increased mortality. The page about vitamin D has been updated.

September 2008: ASBMR abstracts

2008 ASBMR online abstracts

Subtrochanteric fractures and alendronate

Abrahamsen Subtrochanteric And Diaphyseal Femur Fractures in Patients Treated with Alendronate: A Register-Based National Cohort Study. The Danish hospital registry identified all patients older than 51 who had any fracture except hip. 5187 who were then started on alendronate and remained on treatment for at least 6 months were compared to 11160 controls, matching for age, sex, and location of the fracture. Then they were followed to see how many hip and subtrochanteric fractures occured. The rate per year of subtrochanteric fractures was 0.19% in alendronate group and 0.10% in control; the rate of hip fractures was 1.7% in alendronate group and 1.1% in controls.

Osteoporosis treatments

Cummings A Phase III Study of the Effects of Denosumab on Vertebral, Nonvertebral, and Hip Fracture in Women with Osteoporosis. The abstract did not report any data, and I had to rely on my notes, scribbled as fast as I could while the slides were quickly changed, so some of these numbers may not be 100% correct. This was a double-blind clinical trial of 3 years comparing denosumab to placebo in postmenopausal women aged 60-90 with T-score less than -2.5 but greater than -4, without severe or >2 vertebral fractures. 23% had a vertebral fracture. There were 3906 per group, over 80% completed the study. RESULTS: New vertebral fractures in 7.2% of controls and 2.3% of treated women, with positive effects all 3 years. There was a 20% reduction in nonvertebral fractures and 40% reduction in hip fractures over 3 years. The BMD from 441 patients increased 9% at the spine, and there were no differences in adverse events or serious adverse events.

Cummings The Effects of Lasofoxifene on Fractures and Breast Cancer. The abstract presented 3 year data and the oral presentation included a 2 year extension. This was another large, multicenter study of a new SERM, enrolling 8556 women with osteoporosis aged 59-80. 77% completed the study, 64% remained on the drug. The 0.5mg dose gave best results. RESULTS (5 years): Vertebral fractured decreased 42%, nonvertebral fractures decreased 24%, hip fractures non-significant (35 placebo vs 27 Laso.) Breast cancer showed 81% reduction, all from estrogen positive cancers; the hazard ratio for cardiovascular endpoints was 0.68 which was significant. There were more cases of venous thromboembolism. Hot flashes were increased. Thus, lasofoxifene had beneficial effects on fractures, breast cancer, and cardiovascular disease without an increase in strokes.

Lindsay Histomorphometric and Biochemical Bone Formation Responses to First and Second Cycles of Teriparatide Treatment. Bone biopsies showed increased bone formation when teriparatide was first given (but this was attenuated by prior alendronate). After 3 months on and 3 months off, another cycle also resulted in an increase in bone formation rate.

Saag Teriparatide versus alendronate for treatment of glucocorticoid-induced osteoporosis: 36-month results. This is a continuation of a study; the first 18 months were published. By 36 months the increase in spine BMD was 5.3% with alendronate and 11.0% with teriparatide. New vertebral fractures were seen in 7.7% of alendronate group and 1.7% in teriparatide group.

Glendenning Ergocalciferol Is Not Bioequivalent to Cholecalciferol In Vitamin D Insufficient Hip Fracture Cases. 95 patients with hip fractures and vitamin D less than 50 nmol/L (20 ng/ml) were randomly treated with ergocalciferol (Vitamin D2) or cholecalciferol (Vitamin D3). The serum levels were greater with cholecalciferol. The decreases of PTH were similar.

Eastell Effect of once-yearly zoledronic acid 5mg infusion on fracture incidence in postmenopausal osteoporosis: Subgroup analysis of the Horizon PFT study. Zoledronic acid was most effective in women younger than 70 with higher BMI and better renal function.

FRAX and predicting fractures

Donaldson What proportion of older women would receive drug treatment under the new NOF guidelines? Using data from the Study of Osteoporotic Fractures, they found that these guidelines would recommend drugs for 73% of women older than 65, and for 94% of women older than 75. They concluded that evidence and assumptions underlieing these recommendations should be confirmed before promoting widespread drug treatment of women.

Leslie Osteoporosis diagnosis and incident fracture as a function of prior fractures site in a large clinical cohort. Using data from all bone density tests done in Manitoba and the billing fracture codes, the authors found that the site of prior fracture was important for predicting a future "osteoporotic fracture" (hip, spine, wrist or humerus). Only prior fractures of the spine, humerus, radius/ulna, or femoral neck were associated with future osteoporotic fractures. Adjustment for BMD did not change this very much.

Chevalley Deleterious effect of late menarcheal age on bone microstructure in both distal radius and tibia. Women who had menarche younger than the median age (13 years) had better bone density at both femoral neck and distal tibia compared to women who were older than that age. This was true in women aged 20 as well as aged 45.

PHEX and phosphatonins

Addison PHEX Cleavage of SIBLING-ASARM Peptides as a Mechanism Underlying Osteomalacia in XLinked Hypophosphatemia. They studied osteoblast cultures, in which ASARMS inhibited mineralization, but when PHEX was added they were degraded and mineralization normalized. ASARMS are "acidic, serine- and aspartate-rick motif" peptides, from members of the SIBLING family (small integrin-binding ligand N-linked glycoproteins).

Brownstein Increased Bone Volume and Correction Of HYP Mouse Hypophosphatemia in the Klotho/HYP Mouse. A double-knockout of PHEX and Klotho resulted in high phosphate and very high bone density. The bone volume (by micro CT) was 21% in wild-type, 8.6% in the HYP mice, 32.5% in the klotho-KO mice, and 56% in the double-KO mice.

Other interesting abstracts

Edwards The longevity Gene SIRT-1 independently controls both osteoblast and osteoclast function. Mice with knock-out of SIRT develop lower bone volume; if targeted to the osteoblasts their number is reduced, but targeted to the osteoclasts caused increased numbers of osteoclasts. These findings identify a link between aging and osteoporosis.

Lofgren A three-year school-curriculum-based exercise program in propubertal children increases bone mineral accrual and bone size but do not influence femoral neck structure. The study involved 45 girls and 75 boys, matched to 42 girls and 54 boys on the routine program. The spine bone density was about .8 SD higher in the exercising group.

June 2008: Genetic factors related to bone density and fractures

Styrkarsdottir U. Multiple Genetic Loci for Bone Mineral Density and Fractures. N Engl J Med 2008.

This is the first large study looking at variations in genes to see which ones are related to bone density and fractures. The population was from Iceland, where there is enough knowledge of geneology to do the correct statistical tests. Then the genes that were important in the Icelantic population were checked in groups from Australia and Denmark. They studied 5861 people from Iceland and screened about 300,000 gene variations (single-nucleotide polymorphisms). The important ones were in genes for RANKL, OPS, estrogen receptor, histocompatibility, and some with unknown function.


Details about T and Z scores

May 2008: High resolution MRI shows effect of menopause

Wehrli FW. In vivo magnetic resonance detects rapid remodeling changes in the topology of the trabecular bone network after menopause and the protective effect of estradiol. J Bone Miner Res 2008;23(5):730-40.

This technique has been called a "virtual biopsy" of the bone because the resolution is high enough to see the perforations of trabecular plates that occured in normal women who were recently postmenopausal. See the images on the newly revised pages about estrogen.

April 2008: Sclerostin, osteocytes and mechanical forces

Robling AG. Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/sclerostin. J Biol Chem 2008;283(9):5866-75.

Sclerostin is secreted by osteocytes, particularly when the load on the bone is reduced. But when mechanical forces are applied to the bone, the sclerostin production is turned off. The effect is very localized. This is probably the way that osteocytes control formation of new bone. Read more about sclerostin.

February 2008:Absolute fracture risk

I've been waiting for the WHO fracture risk calculator. The idea of absolute fracture risk isn't really new . . . I've been using it all along. This new calculator has incorporated an impressive mass of data and should be very helpful for doctors and patients. The risk of a fracture is much more important than the category based only on a "T-score" Note: The WHO calculator uses T-scores from young WOMEN. Most of the DEXA printouts from men or other races use T-scores based on MEN or other races. Here is a link to the FRAX and a converter for male T-scores.

Bortezomib: potential new anabolic treatment

Mukherjee S. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest 2008;118(2):491-504.

Roodman GD. Bone building with bortezomib. J Clin Invest 2008;118(2):462-4.

This report of cells implanted into a mouse model shows that a drug used to treat myeloma can induce differentiation of stem cells into osteoblasts. The mechanism is inhibition of the proteasome, which degrades intracellular proteins such as Runx-2 and Gli-3. (the latter stimulates BMP-2). This approach looks promising for myeloma, and potentially for low-turnover osteoporosis as well. I was glad to note that Dr. Roodman re-introduced "OAFs" (osteoclast activating factors), a term I always liked.

Vitamin D levels related to fractures

Looker AC. Serum 25-hydroxyvitamin d and hip fracture risk in older U.S. white adults. J Bone Miner Res 2008;23(1):143-50.

These results are from the NHANES study, and show that low vitamin D levels are associated with fractures. It is important to note that high levels are NOT better than moderate levels. There was no benefit to fractures when vitamin D was above 60 mMol/L = 24 ng/mL. Results are shown on the page about vitamin D .


Vitamin D

January 2008: Calcium intake not related to short-term fracture risk

Nieves JW. Calcium and vitamin D intake influence bone mass, but not short-term fracture risk, in Caucasian postmenopausal women from the National Osteoporosis Risk Assessment (NORA) study. Osteoporos Int 2007.

A study of 76,507 postmenopausal women estimated calcium intake from a questionnaire and asked about fractures 3 years later. The calcium intake was not related to the risk of fractures. Those with life-long highest calcium intakes, however, did have higher bone density. The average calcium in the diet was 600mg/day and the average total calcium intake (food plus supplement) was 900mg/day.


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