Fracture Risk during puberty and why?

Kirmani S, Christen D, van Lenthe GH, et al. Bone Structure at the Distal Radius During Adolescent Growth. J Bone Miner Res. 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19113916 [Accessed January 13, 2009].

In conference today Dr. Kirmani presented his data on the topic of increased fractures in puberty. He noted that in reviewing data gathered over the last 4-5 decades by the Mayo Clinic, there is an increase in fractures during puberty in both boys and girls. Overall, the frequency of fractures is also increasing over this time period.

In order to study this, the group looked at the distal radius (the most common site of fractures in this age group). They used a novel technique of high-res QCT to obtain images that were very close in detail to bone biopsy. By enrolling subjects in different age groups, they were able to gather data regarding the changes that take place in terms of bone.

As seen in the figure, the cortical portion of the bone becomes the weakest during puberty as bone growth occurs. This may be due a delay in the formation of cortical bone as opposed to trabecular bone as overall lengthening occurs. The reasons behind this are unknown but many in the audience suggested a local action of PTH in serving up cortical bone as a source of calcium (similar to that seen in breast feeding).

Regardless of the etiology, due to the lenghtening process without adequate thickening, the bone strength is approximately 1/8 that of the original bone thus leading to increase fractures.

Bisphosphonates INCREASE osteoclast number?

A new study published in NEJM questions the long-held belief that bisphosphonate use promotes osteoclast apoptosis.
This study examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods.

The Results were startling:
The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01).> the number of osteoclasts increased as the cumulative dose of the drug increased (r=0.50, P<0.001).> of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling.

The discussion also has a great explanation as to why this may be occurring. It is too long to add here but to paraphrase, it appears the signal for the osteoclasts to undergo apoptosis is from the calcium they have just absorbed. Since the bisphosphonates inhibit this bone resoption, they stop the signal to enter into apoptosis.

Can read further here...

Update in Male Osteoporosis

This is a great review article on everything new in male osteoporosis by Dr. Khosla. He does a great job of summarizing male osteoporosis by focusing on three main topics: epidemiology, pathogenesis, and management.

Context: Osteoporosis in men is becoming an increasingly important public health problem. One in five men over the age of 50 yr will suffer an osteoporotic fracture during their lifetime, and men who sustain fractures have an increased mortality risk.

Evidence Acquisition: Evidence was obtained by PubMed search and author’s knowledge of the field.

Evidence Synthesis: Studies using computed quantitative tomography and high-resolution peripheral computed quantitative tomography have provided new insights into the bone structural changes with aging in men, including the somewhat surprising demonstration of significant, ongoing trabecular bone loss starting in young adult life. In addition, there are now data demonstrating that serum estradiol levels are important predictors of fracture risk in men and that there is a threshold estradiol level below which not only bone loss but also fracture risk increases markedly. Criteria for diagnosing and managing osteoporosis in men are also evolving, including the application of the fracture risk assessment tool to derive 10-yr fracture risks in men. Three bisphosphonates (alendronate, risedronate, and zolendronic acid) and teriparatide are currently U.S. Food and Drug Administration approved for the treatment of osteoporosis in men, with a number of new compounds, including a monoclonal antibody against receptor activator of nuclear factor-B ligand, selective estrogen receptor modulators, and selective androgen receptor modulators in varying stages of development.

Conclusions: Despite significant advances, there remain a number of key unresolved issues regarding the pathogenesis and management of male osteoporosis, not the least of which is increasing public awareness of this important cause of morbidity and mortality in men.

Long Term Bisphosphonate Use

This study by Nelson B. Watts and Dima L. Diab from University of Cincinnati is an excellent review of the pharmacodynamics and pharmacokinetics of bisphosphonates and the effect of their long term use. I thought what was striking about this particular article are the recommendations of a drug holiday. This is something many have discussed previously but has not be published significantly.

"Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5–10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time."

Read the full article in Goodreader...

Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet

A Randomized Trial

1. Gary D. Foster, PhD;
2. Holly R. Wyatt, MD;
3. James O. Hill, PhD;
4. Angela P. Makris, PhD, RD;
5. Diane L. Rosenbaum, BA;
6. Carrie Brill, BS;
7. Richard I. Stein, PhD;
8. B. Selma Mohammed, MD, PhD;
9. Bernard Miller, MD;
10. Daniel J. Rader, MD;
11. Babette Zemel, PhD;
12. Thomas A. Wadden, PhD;
13. Thomas Tenhave, PhD;
14. Craig W. Newcomb, MS; and
15. Samuel Klein, MD

+ Author Affiliations

1. From Temple University, University of Pennsylvania School of Medicine, and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; University of Colorado Denver, Denver, Colorado; and Washington University School of Medicine and University of Missouri, St. Louis, Missouri.

Abstract

This article has been corrected. For original version, click "Original Version (PDF)" in column 2.

Background: Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss.

Objective: To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program.

Design: Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936)

Setting: 3 academic medical centers.

Patients: 307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m² (SD, 3.5 kg/m²).

Intervention: A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low–glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d; ≤30% calories from fat). Both diets were combined with comprehensive behavioral treatment.

Measurements: Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study.

Results: Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years.

Limitation: Intensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high.

Conclusion: Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years.

Primary Funding Source: National Institutes of Health.

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Screen for osteoporosis and colon cancer - at the same time?

Found these links in the Endocrine Daily briefing from the Endocrine Society. Interesting pair of news articles describes how CT colonography can also be used to measure bone density.

"The results of the study on 35 people showed the data from the CT colonography images agreed with the subject's DEXA bone mineral density scores normally used to check for osteoporosis."

See news articles in:
Health Day
Medical Page Today

PEI in Thyroid Cancer Recurrence

Thyroid Cancer Conference:

Case: Patient with stable thyroid cancer disease with detectable Tg and Tg-Ab with previous history of thyroidectomy present with neck pain. TSH was 33 and Tg 30. CT evaluation and ultrasound show residual thyroid tissue. With TSH suppression, the Tg dropped to a low level again. The Tg-ab had been stable throughout without any rise.

Question of the options:
1. is this recurrence?
2. options: RAI, thyroid surgery, just followup, or PEI.

Dangers of PEI
1. nerve damage. The laryngeal nerve is very delicate. alcohol can cause permanent damage to this nerve.
2. A large amount of alcohol is needed to treat a large lesion
3. Not currative.

In terms of recurrence, Tg-ab may be a better marker of disease than Tg in this case?

On CT, the thyroid tissue will light up like bone.