A scientific advisory committee voted (by a narrow margin) to restrict use of calcitonin due to a slight increased risk of cancer when results from all the calcitonin studies were combined. Noel Weiss, an epidemiologist from the University of Washington, was asked to put these findings into context and he stated that "the nature of the available data provide no more than a hint that an increase in risk might be present." Here are some of the presentations. Here is a link to background information prepared by FDA staff. The FDA will consider this issue later this year.
Schierbeck LL. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ 2012;345:e6409
This was a randomized, open label trial that lasted 10 years from 1990. The 1006 subjects were recently postmenopausal. The study was stopped early because the Women's Health Initiative results had suggested estrogen was harmful. Followup for another 6 years was done using registries in Denmark. The results showed a benefit from estrogen during the first ten years, with fewer cardiovascular events and no increase in cancer or stroke. During the followup there were still no increases in cancer or heart disease. The same study also showed a reduction in wrist fractures and a reduction in weight gain.
The initial findings of the KEEPS study were presented in October at the North American Menopause Society meetings. This 4 year study compared estrogen to placebo in women who were within 3 years after menopause. The results showed improvement in bone density, and no serious side effects. Unlike the Women's Health Initiative Study (which was done in older women) there was no increase in risk of heart attack or breast cancer. There were benefits to depression and hot flashes. There was a trend towards improvement in the coronary artery calcifications. I think this study supports using estrogen in women with low bone density at the time of menopause. The link to the study website is KEEPS study.
Read the section about estrogen for more information.
Imel et al. Iron Modified Plasma FGF23 Differently in Autosomal Dominant Hypophosphatemic Rickets and Health Humans. J Clin Endocrinol Metab Nov 2011
Autosomal dominant rickets becomes worse with iron deficiency. The osteocytes in both normal people and those with a mutation in FGF23 will secrete more FGF23 when there is iron deficiency. However, in the normal people the FGF23 is degraded, whereas in those with the mutation the FGF23 levels increase and cause phosphate loss.
I have revised the page on Osteomalacia and Rickets. Also updates on the mechanisms of renal phosphate loss and more about NHERF mutations.
Dell RM et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012.
Our paper was just published about the incidence of these fractures. We found 142 cases over 5 years at Kaiser in Southern California. In patients taking bisphosphonates for less than 2 years the incidence was 1.78 per 100,000/yr and after 8 years the rate climbed to 113 per 100,000/yr. Read more about these fractures.
Recently there have been several reports that have re-analyzed previous studies and come to somewhat contradictory recommendations about calcium and vitamin D. One is from the the U.S. Preventive Services Task Force and another from the American College of Physicians Journal Club (to be published June 19), both based on an analysis by Chung. The study found only a modest benefit on fractures with combinations of calcium and vitamin D. The USPSTF now recommends against taking supplements because they don't prevent enough fractures. Meanwhile the Institute of Medicine recommends that women should have 1200mg of calcium a day for best bone health. There are also some studies suggesting increased calcifications in the blood vessels with too much supplementation.
I have read these various reports and think that for now the best advice is to try to get at least 500mg of calcium from the diet in the form of dairy products such as yogurt, cheese, and milk. If possible, 3 servings of dairy and some green calcium-containing vegetables will provide all the calcium that is needed. If that is too difficult, then 500mg of supplement should be safe and is probably better than an inadequate intake.
It is important to remember that these new reports are largely still based on the Women's Health Initiative, which did not show a benefit for fracture prevention. However, the women were already taking an average of 1100mg of calcium a day, so an extra 1,000 mg did not help. The bones need an adequate amount of calcium, but once that is achieved, extra will not go into the bones. More information about calcium contents and calcium is on the calcium page.
You can review the abstracts on the ASBMR page
Arasu: Sclerostin and risk of hip fracture in older women.
Serum sclerostin was measured from serum stored in 1988 (at -190 ”C) in 228 women with hip fractures and 227 randomly selected controls. Relative risk in highest quartile was 3.4, so higher sclerostin levels are associated with greater risk of hip fracture.
Armamento-Villareal: Sclerostin mediates the skeletal effects of weight loss and exercise therapy in older adults.
These investigators did a clinical trial in obese elderly women, who were randomly assigned diet, exercise, diet plus exercise, or no intervention. The bone density decreased in those who lost weight with diet alone, but not with those who lost weight with diet + exercise. The serum sclerostin levels increased in the diet-alone group. Thus, sclerostin may mediate bone loss in women with voluntary weight loss.
Devogelaer: Sclerostin antibody increased bone mass and reduced fractures in osteogenesis imperfect mice.
Increased cancellous and cortical bone mass throughout the skeleton and reduced fracture number by 56%.
Gossiel: The Effect of Glucocorticoid Therapy on Regulators of Bone Formation in Postmenopausal Women Treated with Teriparatide or Alendronate.
53 postmenopausal women on steroids (mean age 63 years) were randomized to teriparatide or alendronate. Blood tests compared with healthy women mean age 38. Sclerostin was higher in the osteoporotic women, and Dkk1 was lower. There was no change with either treatment in serum sclerostin or Dkk levels.
Yavropoulou: Serum Sclerostin Levels Across a Wide Range of Bone Turnover.
in 94 patients with Paget's disease and 28 with prostate cancer and 77 healthy individuals, the serum sclerostin levels were higher in the patients with disease. The levels correlated with P1NP (r = 0.29).
Spatz: Treatment with Sclerostin Antibody Increases Bone Mass and Strength During Hindlimb Unloading.
They treated mice for 21 days who were normal or had hindlimb unloading. Sclerostin antibody can increase bone mass by increasing bone formation in normal loaded or under-load bones, though it seems that sclerostin antibody is more effective in increasing bone mass in normally loaded bone than in under-loaded bones.
Azzam: Paget's disease-causing mutations in sequestosome-1 impair autophagic protein degradation.
Using cell lines with a mutation in p62, they found increased protein degradation. This was worse when autophagy was stimulated by amino acid starvation and better when autophagy was blocked with the inhibitor bafilomycin. These are the same mutations that can be seen in Paget's disease.
Daroszewska: Mutations of SQSTM1 Cause dysregulation of the autophagy pathway in osteoclast precursors and are responsible for development of intranuclear inclusions in Paget's Disease.
In a mouse model of Paget's disease with a mutation, the mice developed a disease like Paget's disease and the osteoclasts in the focal lesions contained intranuclear inclusion bodies similar to those with Paget's, and they had markers of autophagosomes (not viral particles).
Wang: Measles Virus Nucleocapsid Protein induces Autophagy in Osteoclasts: Implications for the Pathogenesis of PagetÕs Disease of Bone.
They examined the impact of MVNP expression on autophagy in the OCL generated in vitro from the bone marrow monocytes of wild- type and TRAP-MVNP transgenic mice. Autophagy was induced during osteoclast differentiation.
Holzer: Parathyroid Hormone 1-84 Accelerates Fracture Healing in Pubic Bones of Elderly Osteoporotic Women.
21 patients received a once daily injection of 100µg PTH 1-84 starting within two days after admission to the hospital, 44 patients without PTH treatment served as a control group. In all 21 patients treated with PTH 1-84 pelvic fractures were healed at a mean of 7.8 weeks, whereas in patients with no PTH treatment fractures had healed after 12.6 weeks
Cohen: Teriparatide in premenopausal women with idiopathic osteoporosis: A paired transiliac bone biopsy study.
In 11 subjects after 18 months, the bone volume increased from 21.1 to 29.2. The trabecular number and wall width increased and trabecular separation decreased. The bone mineralizing perimeter was 3.4% at both baseline and 18 months. The improvement in the structural measurements suggests that there was an earlier increase in bone formation that returned to baseline after 18 months.
Fahrleitner-Pammer: Increase of serum P1NP is associated trabecular microstructural improvement in patients on teriparatide pretreated with alendronate.
In paired bone biopsies from 29 patients previously treated with alendronate and 16 treatment naive patients, the change in P1NP at 12 months correlated with the change in bone volume and trabecular thickness and number. This correlation was similar in both groups, and those pre-treated with alendronate also showed an increase in the P1NP and bone volume.
Farahmand: Osteoanabolic Treatment of Adult Osteogenesis Imperfecta with Teriparatide.
This was an open-label observational study in 12 patients, mean age 45 yrs, during 18 months. The bone density increased 11.4% at the spine, 7.1% at the hip, with only one new vertebral and 2 non-vertebral fractures, and decreased back pain.
Nakamura: Effect of Weekly Teriparatide in Patients with Osteoporosis.
In Japanese patients (65-95 years old) with primary osteoporosis, a randomized, double-blind, placebo-controlled trial was conducted in 578 patients with 1-5 prevalent vertebral fractures and low BMD for 72 weeks. The new vertebral fractures were 3.1% in weekly teriparatide vs 14.5% in placebo. Bone density also increased in spine 6.7% vs. 0.3% and hip 3.1% vs. 0.1%.
Maravic: Subtrochanteric/femoral Shaft Versus Hip Fractures: Incidence and Identification of Risk Factors.
The incidence of hip fractures in the French National Database from 2002 to 2009 decreased significantly from 4368 to 4044 per million in women increased in men. In contrast, the incidence per million of ST/FS increased significantly in both genders.
Morin: Use of Oral Bisphosphonates and the Risk of Subtrochanteric and Diaphyseal Fractures in Older Men and Women.
Using the Province of Qubec, Canada, administrative databases identified cases from 2005-2008 who were older than 65. There were 973 cases of subtrochanteric or diaphyseal fractures and 8677 hip fractures. Compared with no use, treatment with bisphosphonate for ³ 4 years duration was associated with a three-fold increase in the risk of sustaining a subtrochanteric or diaphyseal fracture.
Yang: Early detection of lateral cortical lesions in atypical subtrochanteric fracture using dual energy X-ray absorptiometry hip images.
In 47 women with atypical fractures, the images from DXA scans showed changes of external periosteal callus, internal medullary callus, combined callus, or diffuse cortical thickening.
Binkley: Results of the ORACAL trial: a phase 3 randomized trial of the safety and efficacy of orally administered recombinant salmon calcitonin tablets in postmenopausal women with osteoporosis.
The trial lasted 48 weeks. 189 women took oral calcitonin, 140 nasal, and 82 placebo. THe spine density increased by 1.53% with oral, 0.76% with nasal and 0.47% (NS) with placebo.
Cosman: Who is at highest risk for new vertebral fractures after 3 years of annual zoledronic acid and who should remain on treatment? .
1223 women who had taken zoledronic acid for 3 years were randomly given 3 more years or placebo. Those with BMD T-score lower than -2.5 at 3 years, or those who had a fracture during the first 3 years, had significantly lower vertebral fracture rates with 6 years compared with 3 years.
Finkelstein: Hypogonadism in men and hypogonadism with estrogen removal: Effects of androgens and estrogens on bone resorption in young adult men.
The men were treated with goserelin to block endogenous testosterone and replaced with varying doses of testosterone for 16 weeks. Half of them also had estrogen blocked. The resorption marker CTX increased in all groups with low estrogen, but it was worse in those who also had low testosterone. The NTX also increased in those with normal estrogen but low testosterone, but a substantial decline in testosterone was needed. The skeleton in adult men appears to be more sensitive to a decline in estrogen than to a fall in androgens.
GEFOS Consortium: Large-scale meta-analyses of Genome-Wide Association Studies for Fracture Risk.
In 53,016 adults, including 9185 fracture cases, GWAS found strongest signal, albeit with modest effect size, at a gene coding for a protein of unknown function. Also a variant in LRP5 and several other genes known to cause skeletal monogenetic disorders.
Glendenning: Three Monthly, Oral 150,000 IU Cholecalciferol Supplementation Effects On Falls, Mobility and Muscle Strength in Older Postmenopausal Women.
This was a randomized clinical double-blinded trial with dose every 3 months for 9 months. There were no changes in the grip strength or rate of falls (31% vitamin D vs. 27% placebo) despite increases in the vitamin D levels.
Malluche: Low bone turnover and abnormal collagen crosslinking in women with atraumatic fractures and near-normal BMD.
Bone biopsies from 10 pre or peri-menopausal women 10 women, compared with 10 controls, showed higher bone density in fracture cases. Bone volume was not different, but number of osteoblasts and bone formation rate were lower and cross-linking by FRIR spectroscopy showed more enzymatic cross-linking. These findings are different from conventional postmenopausal osteoporosis.
Motyl: Brown Fat Regulates Bone Mass Through Modulation of Sympathetic Tone.
The investigators used mouse models with no brown fat. They had low body temperature, greater sympathetic tone, and very low bone mass. The loss of bone was attenuated by beta-blockers.
Tebbin. A novel syndrome characterized by intermittent hypercalcemia, hypercalciuria, elevated serum calcitriol and undetectable 24,25-dihydroxyvitamin D concentrations, nephrolithiasis, osteoporosis, and mutations in the CYP24A1 gene.
These findings were seen in a 44 year old man, and his 3 year old daughter.
Virnig: Incidence of and predictors of false negative self-reports of hip fractures in cohort studies.
In the Study of Osteoporotic fractures, hip fractures were self-reported by subjects from post cards sent every 4 months, with 99% response rate. When these were matched to the fractures found from Medical claims data, there were 161 women fractures not reported out of 770 women with fractures, for a false-negative rate of 20.9%.
Cauley JA. Serum 25 hydroxyvitamin (OH)D and clinical fracture risk in a multiethnic Cohort of women: The Women's health initiative (WHI). J Bone Miner Res 2011.
This analysis from the Women's Health Initiative found a higher risk of fracture in Black women whose serum vitamin D level was lower than 17 ng/ml. This is very different from White women who had a higher risk of fracture with low vitamin D. This suggests that recommendations for vitamin D should be different in White and Black women. See page about vitamin D.
Schilcher J. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011;364(18):1728-37.
From Sweden, Schilcher reviewed records from all women older than 55 in 2008. Using registry data, there were 1315 diaphyseal fractures, but after radiographic classification there were only 322. Of these, 59 had an atypical appearance, which was seen in 13 of 1,437,820 nonusers and 46 of 83,311 bisphosphonates users (age-adjusted relative risk of 47). 85% of these occurred after more than 2 years of bisphosphonate use. The incidence was 8.5 per 10,000 patients/year with over 2 years of exposure.
Park-Wyllie LY. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. Jama 2011;305(8):783-9.
A study of a data-base from Ontario, Canada found an increased risk of diaphyseal femur fractures in patients who had taken bisphosphonates. The study included only women who had started bisphosphonates when they were older than 68, so many fractures would have been missed.
Banffy MB. Nonoperative versus Prophylactic Treatment of Bisphosphonate-associated Femoral Stress Fractures. Clin Orthop Relat Res 2011.
In this review of fractures from one institution, 5 of 6 incomplete fractures went on to a complete fracture if they did not have surgical stabilization with rods.
I have added many other studies, images and updated the page about atypical femur fractures, including a complete up-to-date review of the literature.
Leslie WD. Spine-hip discordance and fracture risk assessment: a physician-friendly FRAX enhancement. Osteoporos Int 2011;22(3):839-47.
Leslie WD. Absolute fracture risk assessment using lumbar spine and femoral neck bone density measurements: derivation and validation of a hybrid system. J Bone Miner Res 2011;26(3):460-7.
The FRAX risk calculator does not take into account bone density at the spine, but an increased risk of spine fractures can be missed if only the hip is considered. These papers describe a formula to estimate the contribution of spine measurements to the overall fracture risk. This is described on the pages about Fracture risk calculation. See also the page about Discordance between spine and hip.
In November 2010 the Institute of Medicine released their consensus report, which is very similar to the recommendations that were already on this web page. This long and detailed report is available on-line: Dietary Reference Intakes for Calcium and Vitamin D. This is similar to my recommendations (see the page about vitamin D).
Several symposia are available on webcasts. This includes talks about osteoclast biology and new molecular pathways that are similar to those used by the immune system. The epidemiology of hip fractures began with a beautiful talk by Mary Bouxsein about biomechanics of falls and fractures, followed by a discussion of sarcopenia and review of hip fracture rates which are declining in urbanized, "western" countries but increasing in Asian countries. The rountable about disorders of phosphate metabolism was very interesting and based on actual cases.
Treatment for hypophosphatasia: Michael Whyte presented very encouraging results of enzyme replacement for this previously fatal disease. All 13 patients in the trial improved their strength and walking tests.
Vitamin D in men (Johansson): in the MrOS study of 3014 men, levels of vitamin D lower than 77 nmol/l (30ng/ml) were associated with increased mortality. There was no difference in mortality with levels from 30 to 60 ng/ml, which was the highest value reported. Barrett-Connor reported that the average bone density in men with was decreased with a combination of vitamin D lower than 20ng/ml and low sex hormone levels. The effect of low vitamin D alone was not significant.
Whole-body vibration did not improve bone density in postmenopausal women (Slatkovska): In a study of 202 women lasting a year, there was no benefit to whole body vibration. The parameters were 0.3g at 30 or 90Hz. A previous, smaller study by Gilsanz in younger women showed benefit at 0.3g and 30Hz, so the results of this new trial were disappointing. In a related mouse study, Manske was not able to prevent bone loss caused by muscle disuse (using botulinum toxin) by vibration.
Atypical fractures and bisphosphonates There were several presentations about this.
Wang: Using a U.S. database of discharges, found decreased incidence of typical hip fractures and increased incidence of atypical fractures.
Gilchrist: Reviewed X-rays with blinded radiologists, found 11 atypical fractures (4 on alendronate) and 60 typical fractures (8 on alendronate) with a non-significant odds ratio of 3.7. The duration of use was not available.
Girgis: Reviewed all non-hip femur fx in their hospital, found 20 atypical cases and 17 were on bisphosphonates.
Vestergaard: Using a database with codes, they found increased subtrochanteric fractures in bisphosphonate users, but this risk was present before the start of the drugs. They did not review X-rays.
Boskey: FTIR analysis of bones from patients with fractures showed those on bisophonates had narrow distribution of collagen maturity, which might make it easier for cracks to develop.
Drake: The incidence of non-hip femur fractures in Olmstead County increased between 1984 and 1996, which was coincidental with introduction of alendronate.
Ott: Data from Kaiser California, with 2.6 million patients, showed that the incidence of atypical femoral fractures increased with duration of bisphosphonate use, from 2 per 100,000 to 78 per 100,000 at 8 years.
Stress reactions in military recruits (Evans): Using 2-D DEXA of the tibia, they showed that men with stress reactions had higher bone density, but lower bone area. This is another reminder that BMD is not the only factor in predicting fractures.
Sclerostin Antibody in mice with disuse (Robling): This antibody protected the skeleton of the mice. (Moedder) In women and elderly men, estrogen, but not testosterone, decreased the sclerostin levels. (Drake) in patients treated with intermittent PTH, sclerostin levels decreased.
Zoledronic acid: 3 vs 6 years (Black): In an extension study, 1233 women who had used zoledronic acid for 3 years were randomized into 3 more annual infusions vs. placebo. The hip bone density was 1% higher in the zol. group. Spine bone density was done in only 100 subjects and was 2% higher (not significant) in the zol. group. The bone formation markers remained suppressed in both groups. Vertebral fractures in 6.2% (placebo) vs 3.0% (zol.), and non-vertebral fractures in 7.6% (placebo) vs. 8.2% (zoo).
N-telopeptide at menopause predicts fractures (Cauley): In 2090 women followed for 7.6 years, the urine NTX at baseline was higher in those who subsequently developed a fracture.
Serotonin and LRP5 (Williams): Genetically altered mice with no LRP5 or LRP6 in the osteoblasts had some poor bone formation, but when BOTH were knocked out there was severe loss of bone. (Warman): Presented a series of studies about serotonin levels in LRP5 knock-out mice. They did develop bone loss when this was confined to osteoblasts. This was in contrast to previously published studies by Karsenty and Ducy. (Robling) Showed that LRP5 mutant mice (with the high-bone-mass mutation G171V) were protected against bone loss induced by Sost overexpression.
Gut microbiota (Sjogren): This was a really novel idea. The bacteria in the gut are involved in fat regulation. Mice in sterile conditions had better bone mass, and also lower serum serotonin levels. When germ-free mice were then colonized at 3 weeks, they had ordinary bone density.
Nitroglycerin improved bone density (Jamal): In a randomized clinical trial for 2 years, bone density improved with transdermal nitroglycerin ointment. 239 women completed the trial.
ASBMR task for on femur fractures
This is a report that acknowledges a risk of femur fractures in patients with long term use of bisphosphonates. Most of this information has already been on my web page. There is new information from our own abstract, but we were asked not to report about this until after the October ASBMR meeting.
Green J. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. Bmj 2010;341:c4444.
Cardwell CR. Exposure to oral bisphosphonates and risk of esophageal cancer. Jama 2010;304(6):657-63.
These two papers were both from the same large database from the UK, and they reached different conclusions. The JAMA paper used a cohort design for their analysis and found no relationship between bisphosphonates and cancer. The BMJ paper used a nested case-control design, and they had longer follow-up. They found that the risk for cancer of the esophagus was twice as high when patients took the bisphosphonates for longer than 3 years. The actual rate was about 1 in 1000 persons over 5 years in the control group and 2 in 1000 persons over 5 years in the bisphosphonate users. More about bisphosphonates
Bolland MJ. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. Bmj 2010;341:c3691.
This paper has been well publicized and has led to many comments and criticisms from osteoporosis physicians. The authors found a modest increase in myocardial infarction (heart attacks) in those who were taking calcium supplements. This was a meta-analysis of 15 clinical trials of calcium (but not with vitamin D). Of note, there was no risk in the patients whose total calcium intake was lower than 1400 mg/day. I have been recommending a total intake of 1200mg/day for fracture prevention, based on my review of studies about osteoporosis, so this paper (even if it is true) does not change the recommendations on my page about calcium.
Sanders KM. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303(18):1815-22.
In this randomized clinical trial of 2256 older women, a dose of 500,000 units of vitamin D3 (cholecalciferol) once a year for 3 years did not help with fractures or falls. In fact, there were MORE fractures in the treated group than in the placebo group.
Michaelsson K. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr 2010.
The risk of mortality was significantly increased at both low and high blood levels of vitamin D. The range with the lowest mortality was 24 to 34 ng/ml (60 to 85 nMol/L). This curve in men was similar to the curve from women in NHANES.
Byers T. Anticancer vitamins du Jour--The ABCED's so far. Am J Epidemiol 2010;172(1):1-3.
The July issue of this journal was devoted to careful analysis of the relationship between vitamin D and various cancers. This editorial should be read by everybody who has been advocating huge doses of vitamin D. Overall high levels of vitamin D do not prevent cancer. More details are on the page about vitamin D.
This new treatment was designed specifically to block bone resorption. A new web page has details, a summary of clinical trials, diagrams of the physiology, and references: Denosumab
Schwartz AV Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: The FLEX trial. J Bone Miner Res. 2010.
I have discussed details about the FLEX study of long-term alendronate, which has been misquoted in the recent literature.
Langdahl BL. Teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: an analysis by gender and menopausal status. Osteoporos Int 2009.
Aspenberg P. Teriparatide improves early callus formation in distal radial fractures. Acta Orthop 2010;81(2):236-8.
The study in patients with steroid-induced osteoporosis shows a better vertebral fracture rate with teriparatide. This makes physiological sense because steroids cause low bone formation. The main problem is the expense and inconvenience of this treatment, and the lack of longer-term followup. The fracture healing studies are all very preliminary but of great interest to those of us who care for patients. The page about teriparatide has been updated.
Recently there have been several very large studies that have not found a protective effect of vitamin D on cancer risk. These are summarized on this revised page: Vitamin D
Still more about Subtrochanteric fractures.
This is part of the debate about the long-term safety of bisphosphonates. I have made an animated explanation of some of the poorly understood aspects of bone formation and how theoretically medications could effect the bone. This is a bit on the difficult side, but hopefully will help to explain activation frequency and BMU birthrate. Check it out!