Treatment of osteoporosis - potential therapiesJohnell O. Predictive value of BMD for hip and other fractures. J Bone Miner Res 2005;20(7):1185-94.
This meta-analysis included 9891 men and 29,082 women from around the world. The results are shown on the new page about bone density and fracture risk.
Benito M. Effect of testosterone replacement on trabecular architecture in hypogonadal men. J Bone Miner Res 2005;20(10):1785-91.
Men with osteoporosis were treated with testosterone, and bones evaluated with micro-MRI. The images are incredible and are shown (with permission) on the page about male osteoporosis
Deal C. Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J Bone Miner Res 2005;20(11):1905-11.
The combination of teriparatide and raloxifene was synergistic, which was not seen in similar trials using alendronate. The trial lasted only 6 months, so it will be important to know if these results continue to be beneficial for a longer duration.
Cosman F. Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 2005;353(6):566-75.
This is the first publication about "cyclical-intermittent" PTH, which suggests that the cyclical treatment is as effective as the daily treatment for at least 15 months. The follow-up was presented as an abstract in September (see below)
The Intermittent PTH page has been upgraded to include the new trials and combination therapies.
Treatment of osteoporosis - potential therapies
Effects of PTH Rechallenge 1 Year after the First PTH Course in Patients on Long-Term Alendronate.
F. Cosman, J. W. Nieves, M. Zion, N. Barbuto, R. Lindsay
This is a continuing study of patients who had received intermittent PTH a year ago, and they showed a new increase in bone biochemical markers and bone density with a repeat course.
AAE581, a Novel Cathepsin K Inhibitor, Protects against Ovariectomy-Induced Bone Loss in Non-Human Primates, in Part by Stimulation of Periosteal Bone Formation
C. Jerome, M. Missbach, R. Gamse
Cathepsin is made by osteoclasts and inhibitors are mainly anti-resorbing, but there may be some other effects as suggested by this study.
Sclerostin Monoclonal Antibody Treatment of Osteoporotic Rats Completely Reverses One Year of Ovariectomy-Induced Systemic Bone Loss
K. Warmington, M. Ominsky, B. Bolon, R. Cattley, P. Stephens, A. Lawson, D. Lightwood, V. Perkins, H. Kirby, A. Moore, M. Robinson, P. J. Kostenuik, W. S. Simonet, D. L. Lacey, C. Paszty
This is an exciting possible new treatment, because the sclerostin is made only in osteocytes, so this anabolic treatment would be targeted to the skeleton.
Enhancement of Bone Formation by Small Molecule Compounds that Disrupt Dkk-LRP5/6 Interaction.P. Liu, Y. Zhang, X. Li, J. Zheng, D. Wu
These authors tested a wide variety of compounds to identify some that enhance bone formation in mice. This could be another anabolic treatment involving the Wnt-signalling pathway.
Still more about Wnt signalling
Dkk Proteins Control Osteoblast Function and Bone Formation both In Vitro and In Vivo
G. Rawadi, S. Roman-Roman, K. Boulukos, F. Morvan, P. Martin, S. Pinho4, P. Pognonec, P. ClÚment-Lacroix, C. Niehrs, R. Baron
There are at least 3 Dkk proteins, which control osteoblast differentiation and bone formation. Dkk binds to Kremen and ties up LRP5, thereby inhibiting Wnt signalling. Dkk 1&2 cause cells to differentiate into adipocytes instead of osteoblasts. Dkk1 knock-out mice homozygotes do not have heads and are not viable (remember that Dickkopf means "thick head"), whereas heterozygous knock-out mice had increased bone volume, more trabecula, increased bone formation and increased ultimate strength on biomechanical testing!
Suppression of Dkk Is Not Essential for PTH-Mediated Activation of Canonical Wnt Signaling in Bone
J. Guo, E. Schipani, M. Liu, F. R. Bringhurst, H. M. Kronenberg.
Mice overespressing Dkk1 were mated to Jansen transgenic mice that had increased PTH receptor. PTH activated the Wnt-signalling pathway, even when there were high levels of Dkk1.
Blocking Dkk Activity in Primary Myeloma-Bearing SCID-rab Mice Is Associated with Increased Osteoblast Activity and Bone Formation, and Inhibition of Tumor Growth
S. Yaccoby, F. Zhan, B. Barlogie, J. D. Shaughnessy
Dkk1 Modulates Osteoclastogenesis and Bone Resorption: Implications for Myeloma Bone Disease.B. O. Oyajobi1, A. Gupta, A. Flores, C. Wideman, C. Shipman, G. R. Mundy, I. R. Garrett
These two papers extend our knowledge about Dkk in myeloma. Not only does the Dkk suppress bone formation, it also increases bone resorption. And blocking the Dkk not only helps the bone, but inhibits tumor growth as well.
A variety of abstracts with clinical importance
MRI Based Virtual Bone Biopsy Detects Large One-Year Changes in Trabecular Bone Architecture of Early Postmenopausal Women
G. A. Ladinsky, B. Vasilic, A. M. Popescu, B. Zemel, A. C. Wright, H. K. Song, P. K. Saha, H. Peachy, P. J. Snyder, F. W. Wehrli.
These MRI exams have incredible resolution, you can actually see trabecular structures from one scan to the next - - - and when you see the perforations caused by estrogen deficiency it is easy to understand how osteoporosis develops.
Successful Transplantation of Infantile Hypophosphatasia Using Bone Fragments and Cultured Osteoblasts
R. Cahill, S. Perlman, S. Mumm, W. H. McAlister, M. P. Whyte
An infant girl with lethal disease was given transplanted bone fragments from her father, directly into the bone, and 5 years later she was doing well. The photograph of the little girl was the best slide of the meeting.
Homozygous Loss-of-Function Mutation in the Renal Sodium-Phosphate Co-Transporter NaPi-IIc (SLC4A) Leads to Isolated Renal Phosphate-Wasting in a Large Consanguineous Kindred with Hereditary Hypophosphatemic Rickets with Hypercalciuria
C. Bergwitz, N. M. Roslin, J. C. Loredo-Osti, M. Tieder, H. Abu-Zahra, M. Fujiwara, K. Morgan, H. S. Tenenhouse, H. JÄppner.
It seemed that this disease should have been caused by a mutation in the NaPi-IIb transporter, but previous studies could not find it. The investigators kept looking and found the mutation in the NaPi-IIc transporter.
Risedronate and Alendronate Similarly Suppress Remodeling and Increase Microdamage in Beagles after Year of Treatment at Clinical Doses
M. R. Allen, K. Iwata, R. Phipps, D. B. Burr
Previous studies showed that high doses of bisphosphonates caused microdamage - now the results are extended to low doses. The material stiffness was increased in the bone, and the toughness was not significantly different from control. Interestingly, the changes in toughness did closely match those predicted by the mineralization density.
Vascular Calcification Stimulated by Chronic Kidney Disease Is Reversible Linked to Stimulation of Skeletal Modeling
G. Saab, S. Mathew, L. Chaudhary, K. A. Hruska
The investigators studied mice that develops vascular calcification when they have chronic kidney disease and are fed a high-fat diet. The mice were treated with BMP-7 and their bone formation increased and the vascular calcification decreased. They concluded that the increased bone formation caused phosphate to be deposited into bone (where it belongs) and not into the blood vessels.
Skeletal Recovery Following Long-Duration Spaceflight Missions as Predicted by Preflight and Postflight Dual X-ray Absorptiometry (DXA) Scans of 49 Crewmembers
J. D. Sibonga, H. J. Evans, H. Sung, E. R. Spector, V. S. Oganov, A. V. Bakulin, L. C. Shackelford, A. D. LeBlanc.
It took about a year for the bone density to recover in astronauts who had been in space for 4-6 months.
Reduced Mineralization Density of Bone in Premenopausal Women with Idiopathic Osteoporosis
P. Roschger, I. Manjubala, J. G. Hofstaetter, E. Shane, M. A. Donovan, J. Fleischer, D. Dempster4, P. Fratzl, K. Klaushofer.
These results suggest that the bone disease in premenopausal women is distinctly different from ordinary postmenopausal osteoporosis. They will probably have some abnormalities in the bone matrix proteins, and further studies are currently underway.
Glutamine Repeat Mutations Define a New RUNX2 Related Syndrome with Decreased Femoral Neck BMD, Decreased Calcaneal Ultrasound and Increased Risk of Osteoporotic Fracture
A. Stephens, J. Doecke, S. H. Ralston, R. Prince, G. C. Nicholson, N. A. Morrison
The investigators screened 3600 normal subjects from Australia, and found 28 with a mutation in the RUNX2 gene. These people had higher risk of fractures.
Check out the new cases about mistakes in interpreting bone density.
Semenov M. SOST Is a Ligand for LRP5/LRP6 and a Wnt Signaling Inhibitor. J Biol Chem 2005;280(29):26770-5.
Li X. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005;280(20):19883-7.
Balemans W. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 2005;36(6):943-7.
This topic is new and HOT! Learn about SOST now, because it promises to be the next break-through anabolic therapy for osteoporosis. Or just because it is so fascinating. If you have not already read the section about Wnt signalling you should start there. Otherwise go directly to SOST/Sclerostin.
Shao JS. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest 2005;115(5):1210-20.
This related paper shows how Wnt-signalling is involved in cardiac calcifications, which are inhibited with teriparatide.
Delmas PD. Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone Miner Res 2005;20(4):557-63.
Nevitt MC. Risk factors for a first-incident radiographic vertebral fracture in women > or = 65 years of age: the study of osteoporotic fractures. J Bone Miner Res 2005;20(1):131-40.
From the title of the first paper, I thought it would be another article about neglect of osteoporosis (see April's article) but actually it is about difficulties in defining vertebral fractures. The article by Nevitt shows risk factors for a new vertebral fracture and again demostrates the serious prognosis of a mild vertebral fracture. I have updated the section about vertebral fracture prevalence and also a new extensive page about defining vertebral fractures.
Stenson WF. Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 2005;165(4):393-9.
Eight patients without GI symptoms had osteoporosis that failed to respond to alendronate.
Pazianas M. Calcium absorption and bone mineral density in celiacs after long term treatment with gluten-free diet and adequate calcium intake. Osteoporos Int 2005;16(1):56-63.
These patients had decreased calcium absorption even when they were on a gluten free diet .
Read the new page about celiac sprue
Majumdar SR. Incidental vertebral fractures discovered with chest radiography in the emergency department: prevalence, recognition, and osteoporosis management in a cohort of elderly patients. Arch Intern Med 2005;165(8):905-9.
Only 60% of vertebral fractures were included in radiology reports from patients in am emergency room, and only 25% were treated for osteoporosis. This topic was covered in a talk by Dr. Eisman at the National Osteoporosis Foundation meeting in April, and I have included a graph of some of the studies he mentioned on a page about neglect of osteoporosis.
Odvina CV . Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90(3):1294-301.
This is a report of 9 cases who had very suppressed bone formation rates and unusual fractures which did not heal properly. Read more about bisphosphonates.
Lucas GJ . Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent. J Bone Miner Res 2005;20(2):227-31.
This interesting paper lends more support to the genetic theory of Paget's disease. There is a new page about this on the ASBMR bone curriculum web page, along with a new animation of very active bone turnover in this disease.
Scholes D . Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 2005;159(2):139-44.
This longitudinal study showed a significant bone loss in teenagers using DMPA, but also there was substantial recovery after discontinuation.
Reginster JY . Strontium Ranelate Reduces The Risk Of Nonvertebral Fractures In Post-Menopausal Women With Osteoporosis: Tropos Study. J Clin Endocrinol Metab 2005.
This is the most recent report about this new therapy, recently approved in Europe. Stontium has a double-action which inhibits bone resorption and also stimulates bone formation - - possibly by activating the calcium receptors. Other recent articles about this drug:
Kanis JA . Intervention thresholds for osteoporosis in the UK. Bone 2005;36(1):22-32.
This is a cost-benefit analysis to help determine when treatment is cost-effective. This has been added to the Fracture Risk Calculator.
