What was NEW in 2000?
December 2000: Anorexia is more closely related to weight than to estrogen deficiency
Grinspoon, S. (2000). Prevalence and Predictive Factors for Regional Osteopenia in Women with Anorexia Nervosa. Ann Intern Med 133(10): 790-794.
This study of 130 young women with anorexia showed a high prevalence of fractures and of low bone density. The bone density was related to weight at all skeletal sites. Bone density did not differ by use of estrogen.
November 2000: Hip protectors reduce rate of hip fractures
Kannus, P.(2000). Prevention of Hip Fracture in Elderly People with Use of a Hip Protector. N Engl J Med 343(21): 1506-1513.
This study was community-based and involved 1801 frail elderly patients. Those assigned to the hip protector group had half as many fractures. Of 1034 falls, only 4 hip fractures occured while patients were wearing the protectors. (falls).
October 2000: Hydrochlorothiazide Prevents Bone Loss
LaCroix, A. Z. (2000). Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 133(7): 516-26.
At last our study has been published!
Reid, I. R.(2000). Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial. Am J Med 109(5): 362-70. Another randomized trial using a higher dose (50mg/d) in postmenopausal women. After 2 years there were significant differences in cortical bone sites.
I will update the epidemiological studies and other clinical trials for this web site soon. It's time to seriously consider the role of this medication in prevention of bone loss.
September 2000: American Society for Bone and Mineral Research (ASBMR) Annual Meeting
Statins: New studies don't see much benefit using currently available statins
Statins and risk of fractures
T. P. van Staa
Using data from the UK, a total of 218,062 patients had a fracture recorded. The mean age was 52 years and 53% were women. Recent statin use (a prescription in the 6 months before the fracture or index date) was found in 771 of the cases and 651 of the controls. The adjusted odds ratio for current use of statins compared to non-users was 1.01 (95% confidence interval 0.91-1.14). There were no significant differences in fracture risks between simvastatin, pravastatin and atorvastatin. Statin users had fracture risks which were comparable to those using other lipid-lowering agents and those patients with hypercholesterolaemia not treated with medication.
Statin Use and Bone Mineral Density (BMD) in Older Women: The Women's Health Initiative Observational Study (WHI-OS)
J. A. Cauley
In 6,442 women enrolled in the WHI-OS at the three BMD clinical sites; 422 (6.5%) reported statin use at baseline (1993-97). Statin users tended to be older than non-users (65.9 and 63.6 years, respectively). Current hormone use was reported by 42% of users and 46% of non-users. Age and BMI adjusted total hip BMD was significantly higher among users (0.86 g/cm2) compared to non-users (0.84 g/cm2), p=0.02, but there was no difference in total body or lumbar spine BMD. We conclude that longer duration of statins and high statin potency may have modest protective effects on hip BMD in older women.
Comment: This was in the abstract book, but the oral presentation suggested that statins did not significantly improve bone density after adjustment for other known risk factors.
Does Statin Use Reduce Risk of Fracture in Postmenopausal Women? Results from the Women's Health Initiative Observational Study (WHI-OS)
A. Z. LaCroix
In the Women's Health Initiative Observational Study (WHI-OS) of postmenopausal women aged 50-79 years, we compared rates of hip, lower arm or wrist, and other clinical fractures among 7847 current statin users at baseline to rates in 85,876 non-users. 187 hip fractures, 1047 lower arm/wrist fractures and 4041 other fractures occurred. Rates of hip fracture were similar among statin users (1.07/1000 person-years) and non-users (0.83/1000 person-years). Longer duration of use (>3 years) was not significantly associated with fracture risk compared to non-users. Findings were similar for the individual statin agents examined separately. These findings do not indicate that use of currently marketed statin medications has an impact on reducing risk of osteoporotic fracture in the large WHI-OS cohort.
While we're thinking about the heart, more on coronary calcifications
Low Bone Mineral Density (BMD) Is Associated with Coronary Artery Calcification
D. P. Kiel
We examined the relation between BMD and and coronary calcification in 146 men (ages 35-76) and 157 women (ages 35-77) of the Framingham Offspring Study in whom calcification of the coronary arteries was assessed by electron beam computed tomography (EBCT). After adjustment for potential confounders in women, spine BMD (continuous variable) had the strongest inverse association with CC (p=.002). These findings suggest that BMD and CC are related processes, and that low BMD may be a marker of subclinical vascular disease.
Aortic Calcification and Rates of Bone Loss in Older Women
K. E. Ensrud
A subsample of women in the FIT study had measurements of abdominal aortic calcifications. The rate of bone loss over the next 3 to 4 years was measured in the subjects taking placebo. Raw values showed no difference in rate of bone loss in those with calcifications, but adjustment for other factors did show an enhanced loss at the hip.
Bisphosphonates prevent arterial calcifications
Studies in rats who were given large doses of coumadin or vitamin D showed that they developed arterial calcifications. If animals were pre-treated with alendronate, the calcifications did not occur.
Comment: This is not the kind of calcification seen in ordinary coronary artery disease. It is more like calciphylaxis. The effects of aminobisphosphonates on arteriosclerosis are unknown.
Difficulties in interpreting bone density in men
Do Men and Women Fracture at the Same BMD Level?
J. A. Cauley
We studied the BMD and prevalent vertebral fracture (VFx) relationship in 314 men (mean, 73 years) and 2,067 women (age mean, 73 years). 13.7% of men and 18.7% of women had a VFx. The mean BMD among men with a VFx (0.84) was significantly higher than the BMD among women with a VFx (0.71), p<0.001. We examined the prevalence of VFx in men using female specific and male specific quartiles of BMD.
Comment: These data about vertebral fractures are different than data from the Netherlands, which show that hip fractures occur at the same level in men as in women.
Prevalence of VFx In Men by Total Hip BMD quartile
|Male Cutoffs||(<0.84)||(0.84 - 0.96)||(0.96 - 1.05)||(>1.05)
|# of men||78||79||77||80
|# Fx (%)||18 (23)||8 (10)||9 (12)||8 (10)
Use of the WHO Criterion in Men: Is -2.5 the Right Number?
K. G. Faulkner
For all measurements except QCT, the prevalence of T < -2.5 was 4-9%, much less than the 13% estimated lifetime fracture risk in males over 50. T-score thresholds on the order of -2.0 (-3.0 for QCT) yielded BMD prevalence estimates closer to the estimated lifetime fracture risk in men. Diagnostic thresholds near T-scores of -2.0 (-3.0 for QCT) identify a proportion of men more closely aligned with the estimated lifetime fracture risk in males over the age of 50. However, these criteria depend on the skeletal site measured and the technique used.
|T-score Criterion||Fem Neck||Hip Total||L1-L4 Spine||Heel||QCT Spine||Forearm||
More about hip BMD
BMD at Various Sites for the Prediction of Hip Fracture: A Meta-Analysis
These results support the superiority of hip BMD and suggest calcaneal ultrasound may be less predictive than previously reported.
Some interesting new findings
A New Highly Sensitive Assay for Parathyroid Hormone in Primary Hyperparathyroidism
S. J. Silverberg
This study suggests that in patients with normal renal function and mild PHPT: a) the full-length molecule and not its metabolites are preferentially increased; b) S-IRMA is increased in virtually all patients; c) S-IRMA is associated with indices of increased PTH activity (increased Sca,AP, and cortical demineralization). We conclude that the S-IRMA offers significantly greater diagnostic sensitivity in patients with PHPT than other currently available assays.
Leptin Controls Bone Formation Exclusively Through a Central Pathway and at a Dose that has no Effect on Body Weight
It has recently been shown that leptin is the most potent inhibitor of bone formation identified to date in mice. Transgenic mice overexpressing leptin are 25% thinner than wild type mice. In contrast, the apoE-leptin mice have normal bone volume and normal histomorphometry. These results indicate that in vivo and at high dose leptin is able to act peripherally on body weight but not on bone loss.
We infused leptin intracerebral in wild type mice. Interestingly, while 2ng/hr human leptin infusion could not lead to significant body weight loss, it leads to a massive bone loss.
Ipriflavone Has No Effect on Bone Metabolism and Causes Lymphopenia in Osteopenic Women
474 postmenopausal women (63 ± 6 yrs) with low bone mass (vertebral T-score < 2) were randomized to either IP 200mg t.i.d. or placebo for 3 yrs. All participants received a calcium supplement of 500mg/d. Bone mineral density (BMD) of the spine, hip, and forearm was assessed by dual X-ray absorptiometry. The annual percentage change from baseline in BMD of the lumbar spine was virtually similar between the two groups (IP vs placebo after 3 yrs): 0.01% vs 0.23% (p=NS); and similarly in the other sites measured. The response to treatment for HOP/cr and CL/cr was also similar between groups: mean for HOP/cr 8.53 vs 8.95 mg/g (p=NS). The lymphocyte concentration decreased significantly in women treated with IP, and 29 women developed asymptomatic lymphopenia (< 0.5x109/l) during treatment. Of these, 48% had recovered spontaneously by 1 yr, 71% by 2 yrs.
Effect of Hormonal Replacement Therapy Withdrawal on Bone Mass and Bone Turnover: The OFELY Study
In the OFELY study, 137 women, mean age 56 yr, who had been taking HRT at baseline for an average of 3 yr, were followed prospectively for 6 years. 119 of them remained on HRT during the follow-up and 18 stopped HRT in the first 4 years. After discontinuation of HRT, the annual bone loss was -1.4% and -2.9% for distal and ultradistal radius respectively. In contrast, in women who remained under HRT, there was a slight increase of bone markers over 4 years (+13% for OC, p=0.003 and +6% for BAP, ns), no significant change of BMD at the distal and ultradistal radius and a slight increase at the mid radius (+0.73%, p=0.05). The rate of bone loss after withdrawal of HRT was significantly greater than in a group of women from the same cohort and matched by age who never received HRT. We conclude that in postmenopausal women who have been on HRT for an average of 6 years, cessation of treatment results in an accelerated rate of bone loss during the subsequent 4 years as compared to untreated women of the same age.
Comment: This study was based on only 18 women! At the meeting, they showed that the rate of bone loss was not greater than in women who were compared to women right after menopause - - - the women started within 3 years of menopause, so they were having a delayed menopause.
Weight cycling increases fracture risk
M. A. Petit
1065 Canadian people (337 men, 728 women) mean age 60 years.
Importantly, fragility fracture history was significantly related to weight cycling episodes. Among those with 0, 1-3 and > 4 weight-cycling episodes, 20.5%, 27.7% and 29.4%, respectively, reported fragility fractures (G-test two-tailed P = 0.025). In conclusion, weight cycling significantly relates to a history of fragility fracture and to femoral neck and lumbar spine BMD in both men and women in this population-based sample.
1-34 PTH reduces fractures
In a double-blind, randomized, prospective 2-year study of 1637 postmenopausal women with established osteoporosis, vertebral BMD increased by 8.6%,
femoral neck BMD increased by 3.6%, the incidence of new vertebral fractures (vFx)
decreased by 65%, and the incidence of nontraumatic nonvertebral fractures decreased by 53% (lower dose vs. placebo). These changes were seen regardless of baseline age or bone density.
June 2000: World Congress on Osteoporosis 2000
Four full days of information about osteoporosis! The abstracts are available to the public at the National Osteoporosis Foundation website. Here are some highlights:
- Alendronate is effective at preventing bone loss when given as 35 mg once a week (M. Luckey). This is good news to patients who don't like to wait for their breakfast or their morning java. Also, it is less expensive.
July 6, 2000: I just got a letter from Merck informing me that the 40mg dose would no longer be available to pharmacies. I called our pharmacy to get the current pricing. Results: for 30 tablets, 5mg costs $66, 10 mg costs $64 and 40mg costs $155. Thus, for one month of treatment it would cost $66 to take 5mg a day and $22 to take 40mg/week.
- Parathyroid hormone looks promising (F. Cosman). Several studies have been done now which show substantial increases in spinal bone density with PTH injections. The bone density of the hip also increases, and now data shows reduction in fracture rates. These studies which show benefit were all done in combination with estrogen, which seems to protect the cortical bone from the ill effects of PTH, although there might still be a little increase in the cortical porosity.
- Risedronate prevents fractures - sometimes (M. McClung). This medication is similar in many ways to alendronate. In a large hip-fracture endpoint trial, the rate of hip fractures was reduced in postmenopausal women younger than 80 who had established osteoporosis or very high risk. In women older than 80, however, who did not have bone density measurements, there was no reduction in rate of hip fracture. The reasons are not yet clear, but it could be due to the more overwhelming impact of falls.
- Hip protection pads prevent osteoporosis in elderly women as long as they are wearing the pads (JB Lauritzen). These are now available in the US under the brand name "SafeHip"
- Osteoporosis is still ignored Bess Dawson-Hughes gave a talk and showed data from a paper that was in press (I didn't catch the name of the author and will supply it as soon as I find out) in which over 900 chest xrays from a hospital were reviewed. Of the 143 who had compression fractures, only about half were mentioned on the radiologists report, and only about 20 to 25% of patients had the words "fracture" or "osteoporosis" in their medical history. . . and of course, were not getting treated for the condition.
May 2000: NIH consensus conference about osteoporosis
This is the newest consensus statement. It really is not new information but does give a very legitimate review of non-controversial topics, and a list of some of the research that is needed.
April 2000: Bisphosphonates may increase bone microdamage Mashiba (2000). Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Mineral Res 15:613-620.
Here is some evidence for the theoretical cracks that appeared in my animations of the effects of bisphosphonates on bone.
March 2000: Estrogen and alendronate cause similar increases in bone density in postmenopausal women Bone (2000). Alendronate and estrogen effects in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 85:720-726.
This is another study of alendronate, estrogen, neither or both - - - this time in somewhat older women (average age 62). After 2 years total hip was not changed in placebo, increased 4% with alendronate, 3.4% with estrogen, and 4.7% with both. At the spine, changes were higher, as with almost all other studies: 6% with either alendronate or estrogen and 8.3% with both. The combination produced a slight additional increase in the bone density. Notice how the magnitude of changes is different from those seen in younger postmenopasual women.
February 2000: Progestins may enhance risk of breast cancer
Schairer (2000). Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283:485-491
This study of 46, 355 women followed for an average of 10 years (about half of whom were taking hormones) suggested that the risk of breast cancer was only slightly increased with estrogen, but when progestins were added the risk per year increased by 8% compared to women taking no hormones.
January 2000: Estrogen more effective than alendronate in increasing bone density
Ravn, P.(1999). Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med 131(12): 935-42.
This is the 4-year update of the EPIC trial, in which women were randomly given alendronate, placebo, or estrogen. The abstract stated that estrogen results were "similar" to alendronate, but the text states: "Treatment with estrogen-medroxyprogesterone acetate resulted in greater increases in bone mineral density at the spine (p<0.001) and similar increases at the hip (P>.2) and total body (P>.2) and was more effective in maintaining bone mass at the forearm (p<0.001)." Reading from the figure, the results at the spine were: placebo -3%, alendronate +3.5%, estrogen-medroxyprogesterone +5.5%, estrogen-norethisterone +8%. At the forearm: placebo -4%, alendronate -2%, and estrogen 0%.
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what was new in 1999
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