See related commentary by Kanis, page [1829][1]

Since the publication of the Osteoporosis Canada guidelines in 2002, there has been a paradigm shift in the prevention and treatment of osteoporosis and fractures. [1][2],[2][3] The focus now is on preventing fragility fractures and their negative

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2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary

Background: Treatment intervention thresholds for prevention of osteoporotic fractures can be derived from reports from the World Health Organization (diagnostic criteria) and National Osteoporosis Foundation (treatment criteria). It is not known how well these thresholds work to identify women who will fracture and are therefore candidates for treatment interventions. We used data from the National Osteoporosis Risk Assessment (NORA) to examine the effect of different treatment thresholds on fracture incidence and numbers of women with fractures within the year following bone mineral density measurement. Methods: The study comprised 149 524 white postmenopausal women aged 50 to 104 years (mean age, 64.5 years). At baseline, bone mineral density was assessed by peripheral bone densitometry at the heel, finger, or forearm. New fractures during the next 12 months were self-reported. Results: New fractures were reported by 2259 women, including 393 hip fractures; only 6.4% had baseline T scores of �2.5 or less (World Health Organization definition for osteoporosis). Although fracture rates were highest in these women, they experienced only 18% of the osteoporotic fractures and 26% of the hip fractures. By National Osteoporosis Foundation treatment guidelines, 22.6% of the women had T scores of 2.0 or less, or �1.5 or less with 1 or more clinical risk factors. Fracture rates were lower, but 45% of osteoporotic fractures and 53% of hip fractures occurred in these women. Conclusions: Using peripheral measurement devices, 82% of postmenopausal women with fractures had T scores better than �2.5. A strategy to reduce overall fracture incidence will likely require lifestyle changes and a targeted effort to identify and develop treatment protocols for women with less severe low bone mass who are nonetheless at increased risk for future fractures.

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Bone mineral density thresholds for pharmacological intervention to prevent fractures

The Scottish Mental Surveys of 1932 and 1947 collected valid IQ-type test scores for almost everyone born in 1921 and 1936 and attending school on June 1, 1932 (N=89,498) and June 4, 1947 (N=70,805). These surveys are described. This research, using the surveys' data, examined (a) the stability of intelligence differences across the life span, (b) the determinants of cognitive change from childhood to old age, and (c) the impact of childhood intelligence on survival and health in old age. Surviving participants of the Scottish Mental Surveys were tested, and the surveys' data were linked with public and health records. Novel findings on the stability of IQ scores from age 11 to age 80; sex differences in cognitive aging; the dedifferentiation hypothesis of cognitive aging; and the effect of childhood IQ on all-cause and specific mortality, morbidity, and frailty in old age are presented.

/pdf/the-impact-of-childhood-intelligence-on-later-life-following-5ckui6xpr1.pdf

The impact of childhood intelligence on later life: following up the Scottish mental surveys of 1932 and 1947.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(02)08827-X.pdf

Treatment of postmenopausal osteoporosis.

Osteoporosis is a complex, multi-factorial condition characterized by reduced bone mass and impaired micro-architectural structure, leading to an increased susceptibility to fractures. Although most of the bone strength (including bone mass and quality) is genetically determined, many other factors (nutritional, environmental and life-style) also influence bone. Nutrition is important modifiable factor in the development and maintenance of bone mass and the prevention and treatment of osteoporosis. Approximately 80-90% of bone mineral content is comprised of calcium and phosphorus. Other dietary components, such as protein, magnesium, zinc, copper, iron, fluoride, vitamins D, A, C, and K are required for normal bone metabolism, while other ingested compounds not usually categorized as nutrients (e.g. caffeine, alcohol, phytoestrogens) may also impact bone health. Unraveling the interaction between different factors; nutritional, environmental, life style, and heredity help us to understand the complexity of the development of osteoporosis and subsequent fractures. This paper reviews the role of dietary components on bone health throughout different stages of life. Each nutrient is discussed separately, however the fact that many nutrients are co-dependent and simultaneously interact with genetic and environmental factors should not be neglected. The complexity of the interactions is probably the reason why there are controversial or inconsistent findings regarding the contribution of a single or a group of nutrients in bone health.

Nutrition in bone health revisited: a story beyond calcium

We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2-treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density (LBMD; measured by dual-energy X-ray absorptiometry [DXA]) and occurrence of new clinical fractures. Serum level of Glu-osteocalcin (Glu-OC) and menaquinone-4 levels were measured at the end of the follow-up period. Serum level of OC and urinary excretion of deoxypyridinoline (DPD) were measured before and after the treatment. The background data of these two groups were identical. The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2-treated group (chi2 = 10.935; p = 0.0273). The percentages of change from the initial value of LBMD at 6, 12, and 24 months after the initiation of the study were -1.8 +/- 0.6%, -2.4 +/- 0.7%, and -3.3 +/- 0.8% for the control group, and 1.4 +/- 0.7%, -0.1 +/- 0.6%, and -0.5 +/- 1.0% for the vitamin K2-treated group, respectively. The changes in LBMD at each time point were significantly different between the control and the treated group (p = 0.0010 for 6 months, p = 0.0153 for 12 months, and p = 0.0339 for 24 months). The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 +/- 0.3 ng/ml and 1.6 +/- 0.1 ng/ml, respectively (p < 0.0001), while the serum level of OC measured by the conventional radioimmunoassay (RIA) showed a significant rise (42.4 +/-6.9% from the basal value) in the treated group at 24 months (18.2 +/- 6.1% for the controls;p = 0.0081). There was no significant change in urinary DPD excretion in the treated group. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule.

Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis

The phenotypes of apolipoprotein E (Apo E) and their relationship with the bone mineral density (BMD) were examined in 284 unrelated postmenopausal Japanese women aged 47-82 years (64.0 ± 1.0 years, mean ± SE). The Apo E phenotype was analyzed by the isoelectric focusing method, followed by immunoblotting. The relationship between the Apo E phenotype and the vitamin D receptor (VDR) gene or estrogen receptor (ER) gene genotypes was also studied in the same population. The Apo E phenotypic frequencies in our population were 9.9% for E3/2, 66.5% for E3/3, 1.8% for E4/2, 19.7% for E4/3, and 2.1% for E4/4. We classified these phenotypes into three categories: Apo E4-/- (E3/2 and E3/3, n = 217), Apo E4+/- (E4/3 and E4/2, n = 61), and Apo E4+/+ (E4/4, n = 6). The age, body weight, body height, and years since menopause were not significantly different among these three categories. The lumbar BMD values in these three groups were significantly different in the order of E4-/- (0.91 ± 0.01 g/cm 2 ), E4+/- (0.85 ± 0.02 g/cm 2 ), and E4+/+ (0.83 ± 0.06 g/cm 2 ) (p = 0.031). The same trend was also observed for the Z score of the total BMD (p = 0.022). The serum level of intact osteocalcin in E4+/+ (15.2 ± 5.7 ng/ml) was higher than in E4-/- (7.7 ± 0.3 ng/ml) or E4+/- (7.7 ± 0.7 ng/ml) (p = 0.004 by analysis of variance). However, there were no other significant differences in the serum or urinary levels of bone turnover markers. Serum cholesterol in the E4+/+ group tended to be higher than in the other two groups (p = 0.05). There were no significant associations of the VDR and ER genotypes with the Apo E4 phenotype. A multivariate linear regression analysis revealed Apo E4 to be a significant, independent predictor of the Z score of the lumbar BMD. The effect of the Apo E4 allele on the Z score of the lumbar BMD (-0.493 ± 0.152) was not significantly different from that in the AAB of VDR (-0.616 ± 0.225) or PPxx of ER (-0.785 ± 0314). In conclusion, the Apo E4 allele is associated with a low bone mass in postmenopausal Japanese.

Association of bone mineral density with apolipoprotein E phenotype.

To clarify what kind of risk factors predict incident fractures in patients treated with bisphosphonates, the authors investigated the relationship between baseline characteristics and incident vertebral fracture in Japanese osteoporosis patients undergoing bisphosphonate treatment. This was a multi-center follow-up study conducted at three centers, in which a total of 251 Japanese patients with osteoporosis (mean age 70.5 years) from the three centers were followed for 3.2 ± 2.0 years. Baseline data, including pre-existing fractures, bone mineral density in the lumbar spine (LBMD), bone metabolic markers, urinary pentosidine, and plasma homocysteine, were evaluated. Changes in LBMD, bone turnover markers, and incident fractures after the treatment were followed. Sixty-one patients developed incident vertebral fractures; this group of patients was older and had lower LBMD, a higher prevalent vertebral fracture number, and higher homocysteine and pentosidine levels than patients who did not develop incident vertebral fractures. Changes in LBMD, urinary N-terminal telopeptides of type I collagen (NTX), and bone-derived alkaline phosphatase showed no significant association with the occurrence of vertebral fractures. Cox’s proportional hazard model demonstrated that age, prevalent fracture, pentosidine, and homocysteine were independent predictors of the incident vertebral fracture rate under bisphosphonate treatment. Higher baseline levels of pentosidine and homocysteine in osteoporosis patients are potential risk factors for incident vertebral fractures when these patients are treated with bisphosphonates. Further clarification is needed to explain why such patients have higher fracture susceptibility.

Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment

There is emergent evidence for divergent associations between 25(OH)D levels and fractures by race and ethnicity, but data on Asian populations are sparse. We investigated this association in a primary care cohort of 1470 postmenopausal Japanese women followed for a mean period of 7.2 years and explored a potential threshold of 25(OH)D. Endpoints were incident vertebral, proximal femur, and long bone fractures. Rate ratios were estimated using multivariate Poisson regression adjusted for lumbar or femur bone mineral density (BMD) less than −2.5 SD of the young adult mean (YAM), age, weight, presence of diabetes mellitus, parathyroid hormone, estimated glomerular filtration rate, prior fracture, back pain, present medications and past medical history. Mean age was 63.7 ± 10.7 years and osteoporosis patients were 41.3 %. The background data of the present participants were almost identical to the subjects participating in the National Health and Nutrition Survey of 2003. Overall, 49.6 % of the subjects had a 25(OH)D value  25 ng/mL, probably leading to the decreasing trend in long bone fracture. Multivariate-adjusted rate ratios of 25(OH)D < 25 ng/mL were 1.01 (95 % confidence interval [CI], 0.84–1.22, p = 0.88) for vertebral fracture, 2.71 (95 % CI 0.94–7.83, p = 0.07) for proximal femur fracture, and 2.20 (95 % CI 1.37–3.53, p < 0.01) for long bone fracture. The respective rate ratios of a BMD level lower than −2.5 SD of the YAM were 1.61 (95 % CI 1.33–1.94, p < 0.01), 1.52 (95 % CI 0.67–3.45, p = 0.32), and 1.54 (95 % CI 1.02–2.33, p = 0.04). In conclusion, 25(OH)D is a leading risk factor for long bone fracture comparable to BMD in Japanese postmenopausal women. The contribution of 25(OH)D to fracture risks is substantial even below 25 ng/mL and is possibly site-specific. We recommend measuring the serum 25(OH)D level in primary care settings.

Serum 25-hydroxyvitamin D below 25 ng/mL is a risk factor for long bone fracture comparable to bone mineral density in Japanese postmenopausal women

To evaluate the possible interaction of metabolic effects in the mevalonate pathway between amino-bisphosphonates (amino-BP) and vitamin K, the serum level of undercarboxylated osteocalcin (ucOC) was measured in amino-BP users in relationship to incident fracture occurrence. Osteoporotic patients (mean age, 70.7 ± 9.1 years; n = 231) treated with alendronate or risedronate were followed for 3.4 ± 2.1 years, and observations regarding the presence or absence of incident fractures in their vertebrae were made based on vertebral X-ray films every year. During the observation period, new fractures were found in a total of 71 patients (incident vertebral fracture, n = 61; the remaining 10 patients had long bone fractures). The baseline data of the patients with incident fractures indicated that incident fractures are more likely to occur in older patients who have a higher number of prevalent vertebral fractures and lower baseline lumbar bone mineral density (LBMD) as compared to patients without incident fractures. There was no significant difference in the changes of LBMD and urinary excretion of NTX after treatment. On the other hand, the serum level of ucOC in patients with incident fractures and with amino-BP treatment was significantly higher (2.75 ± 0.19 ng/ml) than that in patients without incident fractures and with amino-BP treatment (2.28 ± 0.13 ng/ml) (P = 0.038). These results indicate that older age, a greater number of prevalent fractures and higher ucOC levels, and lower LBMD are risks for incident fractures despite use of amino-BP. The time-dependent incident fracture rate was higher in accordance with an increase in the number of risk items (P < 0.001 in log-rank and Wilcoxon tests). In conclusion, measurement of undercarboxylated osteocalcin may be useful for assessing fracture risk in patients receiving amino-BP treatment.

Yumiko Shiraki

Papers

Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis

Association of bone mineral density with apolipoprotein E phenotype.

Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment

Serum 25-hydroxyvitamin D below 25 ng/mL is a risk factor for long bone fracture comparable to bone mineral density in Japanese postmenopausal women

High level of serum undercarboxylated osteocalcin in patients with incident fractures during bisphosphonate treatment