This has now been published: Kanis(2002). International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res 17: 1237-44.
Click to see an interactive map of the hip fracture rates!
These the abstracts that I thought were the most interesting:
High-bone-density gene
This was reported in a talk by Dr. Mark Johnson (who works with Dr. Robert Recker). The gene has been identified as the LDL-receptor-related-protein (LRP-5). More
Frizzled and Wnt-signalling
Secreted Frizzled-related Protein (sFRP-1) Binds to RANKL to Inhibit Osteoclast Formation
K. D. Hausler, N. J. Horwood, A. Uren, J. Ellis, C. Lengel, T. J. Martin, J. S. Rubin, M. T. Gillespie.
Secreted Frizzled-Related Protein (SFRP)-1: A Novel Regulator of Osteoblast and Osteocyte Apoptosis
P. V. N. Bodine, R. A. Moran, H. E. Ponce-de-Leon, S. A. McLarney, J. Green, G. S. Stein, J. B. Lian, B. S. Komm.
Frizzled Related Protein 4 Expression Is Elevated in Tumors Associated With Oncogenic Osteomalacia and Inhibits Phosphate Transport in Vitro
J. Vassiliadis, S. M. Jan de Beur, A. E. Bowe, R. B. Finnegan, M. A. Levine, R. Kumar, S. C. Schiavi.
Low Bone Mass, Low Body Weight and Abnormal Eye Vascularization in Mice Deficient in LRP5, the Gene Mutated in Human Osteoporosis Pseudoglioma Syndrome
R. Levasseur, M Kato, MS Patel, L Chan, G Karsenty.
More about frizzled and the Wnt signalling pathway.
Once a year bisphosphonate
Zoledronic Acid, at a Total Annual Dose of 4 mg, Increases Bone Density at All Sites and Stably Reduces Bone Turnover for One Year when Administered as a Single or a 3-Monthly Intravenous Injection in Postmenopausal Osteoporosis
J. P. Brown, P. Burckhardt, I. R. Reid, Z. D. Horowitz, P. C. Richardson, U. Trechsel
Alendronate does not increase arterial calcifications
A Pilot Investigation Evaluating Progression of Coronary Artery Calcification in Patients Taking Alendronate for Osteoporosis
J. A. Hill, J. G. Goldin, H. Yoon, L. D. Greaser, D. Gjertson, A. M. Emerick, B. Hu, D. R. Aberle, J. S. Adams
The women taking alendronate did not show more calcification than seen in control women with the same degree of initial calcification, as measured by electron beam CT-scanning.
Menopause causes rapid architectural deterioration
Longitudinal Transmenopausal Changes in Three-Dimensional Trabecular Microarchitecture and Connectivity of Human Iliac Crest Bone Biopsies
Y. Jiang, J. Zhao, R. R. Recker, M. W. Draper, H. K. Genant
A vaccine for osteoporosis
A Novel Therapeutic Vaccine That Prevents Pathological Bone Destruction in Models of Osteoporosis and RA
T. Juji, K. Aoki, D. Horie, K. Ohya, M. Herz, A. Gautam, S. Mouritsen, H. Oda, K. Nakamura, S. Tanaka.
This vaccine is again RANK-L, and seems to work in animal models.
RANK-Ligand can stimulate osteoblasts
RANK Ligand Stimulates Anabolic Bone Formation
J. Lam, F. P. Ross, S. L. Teitelbaum. Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
Murine RANK ligand (RANKL), the key osteoclastogenic cytokine, when administered as an amino-terminal glutathione-S-transferase (GST) fusion protein, increased osteoblast activity.
PTH therapy in men
Recombinant Human Parathyroid Hormone (1-34) Therapy Reduces the Incidence of Moderate/Severe Vertebral Fractures in Men with Low Bone Density
E. Orwoll, W. H. Scheele, A. D. Clancy, S. Adami, U. Syversen, A. Diez-Perez, S. L. Myers, B. H. Mitlak.
Medical treatment of hyperparathyroidism
The Calcimimetic AMG 073 Reduces Serum Calcium (Ca) in Patients with Primary Hyperparathyroidism (PHPT)
M. Peacock, D. M. Shoback, W. E. Greth, T. A. Binder, T. Graves, R. M. Brenner, S. A. Turner, R. Marcus.
Manson, J. E.(2001). Clinical practice. Postmenopausal hormone-replacement therapy. N Engl J Med 345: 34-40.
This is a nice review of the controversies surrounding hormone replacement therapy. The discussion of osteoporosis is fairly brief, and does not mention the fact that in women younger than 60, hormone replacement therapy increases bone density more than bisphosphonates. Also, bisphosphonates have been shown to reduce fractures only in postmenopausal women who have osteoporosis. Long-term safety and efficacy of new osteoporosis drugs have not been demonstrated with any studies (because the drugs are too new). It is true that estrogen has not been shown to decrease fractures in a randomized clinical trial (because nobody has done a study with sufficient power to measure this). However, with estrogen there are many large, long-term observational studies which consistently show fracture reduction. By "long-term" I mean 15 to 25 years, because a 50 year old woman is not expected to have osteoporotic fractures for at least 15 years.
Torgerson, D. J.(2001). Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. Jama 285: 2891-7.
These authors tried to get around the fact that there have been no large randomized clinical trials of estrogen for treatment of osteoporosis. The studies in this review were randomized trials, but for other effects, and for most of the studies fractures were not really an endpoint. They suggest that there is a signficant reduction in fractures in women younger than 60, but not in older women. However, the results are heavily dependent upon the HERS trial results (see next article) which was done in women with heart disease who had a low incidence of osteoporosis.
Cauley, J. A.(2001). Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS). Am J Med 110: 442-50.
This is the study of 2763 women with diagnosed coronary artery disease, randomized to estrogen or placebo for 4 years. The clinical (symptomatic) fracture rate was not different between the groups.
Grodstein, F.(2001). Postmenopausal hormone use and secondary prevention of coronary events in the nurses' health study. a prospective, observational study. Ann Intern Med 135: 1-8.
In the Nurse's Health Study, 2489 women had coronary artery disease. The investigators tried to mimic the conditions of the HERS trial (see above) by comparing the incidence of new coronary artery events in women who started estrogen after the diagnosis of heart disease. They found an initial increase in these events in women who took estrogen. However, after several years, the risk reversed. Overall, after 20 years, the risk was .65. I think these are interesting results, which are compatible with the results of the HERS study. However, as we have all heard hundreds of times, an observational study does not exactly compare with a randomized trial. We all need to wait for the Women's Health Initiative to finish. Appartently, after 3 years there has a slight incrase in risk in the women taking estrogen, but it is less than 0.5%. Also, overall the women in the WHI have not had as many coronary artery events as expected from the general population.
Villareal, D. T.(2001). Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. Jama 286: 815-20.
This study confirms previous smaller studies of estrogen in older women. 67 women who were older than 75 years and frail were randomly given estrogen or placebo for 9 months. During this short time, the bone density increased by 4.3% at the spine and 1.7% at the hip in the estrogen group, which was significantly better than in the placebo group.
Lees, B.(2001). The prevention of osteoporosis using sequential low-dose hormone replacement therapy with estradiol-17 beta and dydrogesterone. Osteoporos Int 12: 251-8.
Another study showing benefits of lower doses of estrogen, this time from the United Kingdom, where 575 women were treated for 2 years in a randomized placebo-controlled trial. The older women showed the best response.
Tremollieres, F. A.(2001). Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporos Int 12: 385-90.
Many women have the misconception that they will have abnormally rapid bone loss if they stop taking hormone replacement. The title of this paper sounds worse than the results. The investigators followed 50 women who had been taking hormones since menopause; the duration of follow-up was variable. After they stopped, there was a significant loss of bone density, but it was no greater than the natural loss after menopause. The rapid-loss phase lasted about 2 years. In other words, menopause was delayed. The relative bone density 3 years after cessation was significantly higher than at baseline, which suggests that there was a lasting beneficial effect of the hormones.
Baron, J. A.(2001). Cigarette smoking, alcohol consumption, and risk of hip fracture in women. Arch Intern Med 161: 983-8.
A population-based case-control from Sweeden compared 1328 cases of hip fracture with 3312 controls. Smoking increased risk of fracture by 66%, whereas alcohol intake decreased the risk by 25% (strong beer appeared better than spirits). Women should be cautious about the alcohol results, because heavy alcohol use has been associated with hip fractures in other studies. The risk of hip fractures improved after women stopped smoking, so here is another compelling argument to stop smoking.
Neer, R. M.(2001). Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis. N Engl J Med 344: 1434-1441.
This study has already been mentioned on this page in September, now it is published. I need to update the section on PTH; there are only a few comments in the treatment section.
White, K. E.(2001). The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab 86: 497-500.
The investigators have identified the gene as FGF-23. The protein made by the gene could be a phosphate wasting factor. Click to read more about osteomalacia.
Browner, W. S.(2001). Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 86: 631-7.
Osteoprotegerin is a receptor in the TNF family which blocks osteoclast proliferation. This study suggests that it has functions beyond those in the bone. More about relationships between the cardiovascular system and bone in this web page.
McClung, M. R.(2001). Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 344: 333-40.
This is the largest osteoporosis study to date, with 9331 women. The major endpoint was hip fracture, and in women younger than 80 who had osteoporosis, the rate of hip fractures was significantly reduced with risedronate. In women older than 80, even if they had osteoporosis, there was no significant effect on incidence of hip fractures. This is discussed more in the pages about bisphosphonates
Recently various different studies have shown relationships between fat and bone. It is not clear how these findings are connected to each other, but here are some heavy results:
Parhami, F. (2001). Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res 16: 182-8.
Mice susceptible to artherosclerosis were fed a high or normal fat diet, and those on the high fat diet had significantly lower bone density. This is particularly interesting in view of epidemiological studies that show a higher incidence of osteoporosis in persons with atherosclerosis, cardiovascular disease, or aortic calcifications.
Ricci, T. A. (2001). Moderate energy restriction increases bone resorption in obese postmenopausal women. Am J Clin Nutr 73: 347-352. Jensen, L. B. (2001). Bone minerals changes in obese women during a moderate weight loss with and without calcium supplementation. J Bone Miner Res 16: 141-7.
Two more studies showing even moderate weight loss due to dieting in obese women leads to bone loss. The study from Denmark found a 4.2% decrease in whole body bone mineral and 4.0% decrease in the hip in women after 6 months of a diet which resulted in 5.5% weight loss (average 94 ot 89 kg, or 207 to 196 lbs). The loss in bone density was attenuated by calcium supplementation.
Mundy, G. R. (2000). Secondary Osteoporosis: The Potential Relevance of Leptin and Low Body Weight. Ann Intern Med 133: 828-830.
This provocative editorial accompanied the article about anorexia nervosa which was last month's citation. Leptin is the hormone made by adipocytes, and it is a potent inhibitor of bone formation. Mice who have congenital absence of leptin (ob/ob) are obese and have very high bone density. Leptin makes them lose both fat and bone. As noted in the review of interesting abstracts from last fall, leptin injected into the brain of animals will inhibit bone formation at doses lower than those that cause loss of body weight. But the osteoblasts don't have receptors for leptin, so the effect is indirect, probably the nervous system is involved.
Ducy, P. (2000). The osteoblast: a sophisticated fibroblast under central surveillance. Science 289: 1501-4.
This is a great review of osteoblasts, gives more descriptions of the leptin experiments (which were done by this group). Also, this paper discusses another connection between fat and bone: marrow stromal cells can differentiate into either adipocytes or osteoblasts. One factor that is important in the differentiation of the cells into osteoblasts is the transcription factor Cbfa1 (core binding factor a1). This is further discussed in the article by Nuttall, M. E. (2000). Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis? Bone 27: 177-84. Once differentiated, the mature adipocytes produce a factor which inhibits the osteoblasts. Maurin, A. C. (2000). Influence of mature adipocytes on osteoblast proliferation in human primary cocultures. Bone 26: 485-9.
Corticosteroid-induced osteoporosis is a serious problem that also involves adipocytes. Wang, G. J. (2000). The Nicolas Andry award. The pathogenesis and prevention of steroid-induced osteonecrosis. Clin Orthop: 295-310. This paper reviews findings that show how steroids increase the number of adipocytes.
Therapy for hyperlipidemia might improve bone density. The effects of statins are still not clear, but the largest study (Women's Health Initiative) showed no beneficial effect of statins on fracture rates. This study was presented last fall and is not yet published.