Overview, Vol 15, Issue 3

Only doubt is certain and disbelief worth believing.
Without this courage there can be no learning.
Believe nothing.

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis. Its purpose was to provide readers without easy access to the literature with summaries of the most important literature. We now inhabit a virtual world. Information is instantaneously accessible to all at the tap of a keyboard; understanding is not. In the spirit captured by the anonymous author*, the purpose of this publication is to provide critical evaluation of the most important literature and so to provoke discussion. It is our intention to promote dialogue which examines the quality of information published and so its credibility. The opinions expressed are my own and do not necessarily reflect those of the International Osteoporosis Foundation."

We invite readers to comment on and discuss this journal entry at the bottom of the page.

PDF Version

FREE DOWNLOAD of PIO Volume 15-3 Figures

In this Issue

  1. Life Expectancy After Fracture: The need for long-term antifracture efficacy
  2. Elevated Incidence of Fracture in Women with Invasive Breast Cancer
  3. Exercise in Childhood and Fewer Fractures
  4. Is Any Association Between Testosterone and BMD Genetically Determined?
  5. Marrow Fat
  6. Diabetes and Bone Qualities
  7. Matrix Mineral Density of Trabecular Plates and Rods
  8. Amino Acid Intake and BMD
  9. Adynamic Bone Disease in Renal Impaired Mice
  10. Calcium Intake and Lower Fracture Risk and Mortality
  11. Porosity in Men With Fractures
  12. Sex Hormone Changes During Ageing in Men
  13. Serum Hormonal Binding Globulin and Fracture Risk in Men
  14. Osteocalcin and Glucose
  15. PTH Treatment and Gap Junctions
  16. Sclerostin Antibody Therapy in Glucocorticoid-induced Osteoporosis
  17. Long-term Antiresorptive Therapy
  18. Bisphosphonate Treatment of Osteonecrosis of the Femoral Head
  19. Vitamin D and BMD
  20. Vitamin D and Muscle Strength
  21. Osteonecrosis of the Jaw

Life Expectancy After Fracture
The need for long-term antifracture efficacy

Abrahamsen B, Osmond C, Cooper C.  Life expectancy in patients treated for osteoporosis: Observational cohort study using national Danish prescription data.  J Bone Miner Res 2015;30:1553-9.

Abrahamsen et al tracked scripts for osteoporosis drugs, comorbidity, and deaths in 58,637 patients and 225,084 controls with 10-17 y follow-up. In men <80 y and women <60 y, the risk of dying declined from being increased in the first year to a stable but elevated risk later. In women >65 y, the mortality risk was elevated in the first year of treatment and then was lower than background.

The residual life expectancy of a 50-y old man beginning treatment was 18.2 y and a 75-y old man was 7.5 y. Estimates in women were 26.4 y and 13.5 y, respectively. Thus, the average life expectancy is over 15 y in women younger than 75 y and in men younger than 60 y, highlighting the need for evidence of long-term efficacy.

Figure 1. Death hazard (shown as log HR) as a function of sex and age at beginning treatment, shown separately for the first year of treatment (0–1 y), years 1 to 5 (1–5 y), and years 5+. Conditional Cox proportional hazards model based on 58,637 patients beginning treatment for osteoporosis and 225,084 age- and sex-matched control subjects. Treatment was started in 1996-2003 and deaths tracked to the end of 2013. Reproduced from J Bone Miner Res 2015;30: 1553-9 with permission of the American Society of Bone and Mineral Research.

Elevated Incidence of Fractures in Women With Invasive Breast Cancer

Edwards BJ, Gradishar WJ, Smith ME, Pacheco JA, Holbrook J, McKoy JM, Nardone B, Tica S, Godinez-Puig V, Rademaker AW, Helenowski IB, Bunta AD, Stern PH, Rosen ST, West DP, Guise TA. Elevated incidence of fractures in women with invasive breast cancer. Osteoporos Int 2015; doi:10.1007/s00198-015-3246-3.

Edwards et al assessed 422 women with invasive breast cancer; 79 (28%) sustained fractures at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40/1000 person-years. Women who sustained fractures had a family history of osteoporosis (36.9%, p=0.03) or history of a prior fracture (6/79, p=0.004). Fractures occurred 4.0 y (range 0-12 y) after cancer diagnosis. Fracture cases had femoral neck T-score of -1.2 SD. Fractures most commonly occurred in lower extremities, vertebral, and wrist. Hip fractures accounted for 11% of fractures, occurring at a median age of 61 y.

Lee SJ, Kim KM, Brown JK, Brett A, Roh YH, Kang DR, Park BW, Rhee Y. Negative impact of aromatase inhibitors on proximal femoral bone mass and geometry in postmenopausal women with breast cancer. Calcif Tissue Int 2015;97:551-9.

Lee et al reported 249 early breast cancer patients who underwent QCT in their fifties (mean age 54.3 y), cortical areal BMDs were lower in the aromatase inhibitor (AI) group than in the non-AI group (p<0.05). Cortical thickness of the femoral neck, trochanter, and total hip was lower in the AI group, especially in the superoposterior quadrant. Bone strength of the femoral neck (section modulus and cross-sectional moment of inertia) were lower in the AI group than in the non-AI group (p<0.05).

Exercise in Childhood and Fewer Fractures

Fritz J, Coster ME, Nilsson JA, Rosengren BE, Dencker M, Karlsson MK. The associations of physical activity with fracture risk-a 7-year prospective controlled intervention study in 3534 children. Osteoporos Int 2015; doi:10.1007/s00198-015-3311-y.

Fritz et al documented fractures in 3534 children aged 6-8 y at study start for up to 7 y; 1339 subjects did 40 min of moderate activity daily (intervention) and 2195 had 60 min activity weekly (controls). Incidence rate ratios (IRR) of fractures decreased with each year of the activity (r=-0.79; p=0.04). During the seventh year, IRR was halved [IRR 0.52 (0.27, 1.01)]. The intervention group had a greater gain in total spine aBMD with a mean group difference of 0.03 (0.00, 0.05) g/cm2 and peak flexion torque 180° with a mean group difference of 5.0 (1.5, 8.6) Nm.

Is Any Association Between Testosterone and BMD Genetically Determined?

Shin J, Sung J, Lee K, Song YM. Genetic influence on the association between bone mineral density and testosterone in Korean men. Osteoporos Int 2015; doi:10.1007/s00198-015-3298-4.

Shin et al reported that in 1070 Korean men including, 144 pairs of monozygotic twins and their family members, total testosterone and calculated free testosterone (cFT) were positively associated with BMD. Monozygotic twins showed no association between pairwise difference of testosterone and pairwise difference of BMD. Bivariate variance component analysis showed that total testosterone and cFT had a positive additive genetic correlation with BMD at rib, spine, and arm, whereas SHBG had no significant genetic correlation with BMD. Inverse environmental correlations were seen between total testosterone and BMDs at the lumbar spine and arm.

Marrow Fat

Cohen A, Shen W, Dempster DW, Zhou H, Recker RR, Lappe JM, Kepley A, Kamanda-Kosseh M, Bucovsky M, Stein EM, Nickolas TL, Shane E. Marrow adiposity assessed on transiliac crest biopsy samples correlates with noninvasive measurement of marrow adiposity by proton magnetic resonance spectroscopy (1H-MRS) at the spine but not the femur. Osteoporos Int 2015;26:2471-8.

Cohen et al evaluated premenopausal women, 9 with osteoporosis and 7 normal controls for marrow fat of the iliac crest by bone biopsy and at the lumbar spine (L3) and proximal femur by 1H-MRS. At L3, fat fraction by 1H-MRS correlated with marrow fat variables on iliac crest biopsies (r=0.5-0.8). There were no correlations between fat fraction at the femur and marrow fat on biopsies. Marrow fat was greater at the femur than at L3 and the iliac crest and correlated inversely with total hip and femoral neck BMD by DXA.

Diabetes and Bone Qualities

Farlay D, Armas L, Gineyts E, Akhter M, Recker R, Boivin G. Non-enzymatic glycation and degree of mineralization are higher in bone from fractured patients with type 1 diabetes mellitus. J Bone Miner Res 2015; doi:10.1002/jbmr.2607.

Farlay et al analyzed iliac crest bone biopsies from 5 patients with type 1 diabetes, diabetics without fractures and 5 healthy subjects, all age- and sex-matched. Trabecular bone from fracture cases had higher pentosidine than control (p=0.04) and was more mineralized than diabetics without fractures (p=0.04) and control (p=0.04). Trabecular and cortical bone were no different in pentosidine between diabetics without fractures and control. Positive correlations were found between HbA1c and Pentosidine (r'=0.79, p<0.003), and between HbA1c and DMB (r'=0.64, p<0.02).

Matrix Mineral Density of Trabecular Plates and Rods

Wang J, Kazakia GJ, Zhou B, Shi XT, Guo XE. Distinct tissue mineral density in plate- and rod-like trabeculae of human trabecular bone. J Bone Miner Res 2015;30:1641-50.

Wang et al reported an individual trabecula mineralization (ITM) analysis to determine tissue mineral density (TMD) in plate- and rod-like trabeculae. Plates had higher TMD than rods. The distribution of TMD in plates was lowest in longitudinal plates and the highest TMD in transverse plates. There was a uniform distribution of TMD among rods with respect to orientation. Plates had higher mean and peak TMD, whereas rods had a wider TMD distribution and a larger portion of low mineralized trabeculae. Heterogeneous TMD in trabecular plates influence elastic properties.

Figure 2. Illustration of ITM analysis. (Top) Decomposition of trabecular microstructure into individual trabecular plates and rods along various orientations. (Bottom) Grayscale image of trabecular bone to be mapped to the segmented trabecular microstructure to quantify the TMD of individualplates and rods. Reproduced from J Bone Miner Res 2015;30:1641-50 with permission of the American Society of Bone and Mineral Research.




Figure 3. Distributions of individual trabecula TMD along trabecular orientation from the longitudinal to transverse direction for trabecular plates (left column) and rods (right column) and for femoral neck (top), greater trochanter (middle), and proximal tibia (bottom). Reproduced from J Bone Miner Res 2015;30:1641-50 with permission of the American Society of Bone and Mineral Research.





Amino Acid Intake and BMD

Jennings A, MacGregor A, Spector T, Cassidy A. Amino acid intakes are associated with bone mineral density and prevalence of low bone mass in women: Evidence from discordant monozygotic twins. J Bone Miner Res 2015; doi:10.1002/jbmr.2703.

Jennings et al reported analyses of female monozygotic twin-pairs discordant for amino acid intake (n=135). Twins with higher intakes of alanine and glycine had higher BMD at the spine than their co-twins, with within-pair differences in spine BMD of 0.012 g/cm2 (SE 0.01; p=0.039) and 0.014 g/cm2 (SE 0.01; p=0.026), respectively. Furthermore, in cross-sectional multivariable analyses of 3160 females aged 18-79 y, a higher intake of total protein was associated with higher BMD at the spine (quartile Q4 to quartile Q1: 0.017 g/cm2, SE 0.01, p=0.035) and forearm (Q4 to Q1: 0.010 g/cm2, SE 0.003, p=0.002). Intake of alanine, arginine, glutamic acid, leucine, lysine, and proline were associated with higher BMD at the spine and forearm with the strongest association observed for leucine (Q4 to Q1: 0.024 g/cm2, SE 0.01, p=0.007). When intakes were stratified by source, vegetable or animal, prevalence of osteoporosis or osteopenia was 13% to 19% lower comparing extreme quartiles of vegetable intake for five amino acids (not glutamic acid or proline).

Adynamic Bone Disease in Renal Impaired Mice

Ng AH, Omelon S, Variola F, Allo B, Willett TL, Alman BA, Grynpas MD. Adynamic bone decreases bone toughness during ageing by affecting mineral and matrix. J Bone Miner Res 2015; doi:10.1002/jbmr.2702.

Ng et al studied young and old (4- and 16-months) Col2.3Deltatk mice treated with ganciclovir and pamidronate to create the adynamic bone condition. Ageing controls had a decline in bone formation and resorption with a corresponding deterioration in trabecular bone structure. Bone turnover was severely blunted at all ages in adynamic animals which preserved trabecular bone loss. However, the preservation of trabecular bone mass and structure in old adynamic mice did not rescue deterioration of bone mechanical properties. There was also a decrease in cortical bone toughness in old adynamic mice that was accompanied by a more mature collagen matrix and longer bone crystals.

Calcium Intake and Lower Fracture Risk and Mortality

Khan B, Nowson CA, Daly RM, English DR, Hodge AM, Giles GG, Ebeling PR. Higher dietary calcium intakes are associated with reduced risks of fractures, cardiovascular events, and mortality: A prospective cohort study of older men and women. J Bone Miner Res 2015;30:1758-66.

Khan et al followed 41,514 men and women aged 40-69 y for 12 (1.5) y. Primary outcome measures were time to death from all causes (n=2855), CVD-related deaths (n=557), cerebrovascular disease-related deaths (n=139), incident nonfatal CVD (n=1827), incident stroke events (n=537), and incident fractures (n=788); 12,097 participants eligible for fracture analysis and 34,468 for nonfatal CVD and mortality analyses. Highest and lowest quartiles of energy-adjusted dietary calcium intakes represented unadjusted means (SD) of 1348 (316) mg/d and 473 (91) mg/d, respectively. There were 788 (10.3%) incident fractures, 1827 (9.0%) incident CVD, and 2855 people (8.6%) died. Comparing the highest with the lowest quartile of calcium intake, HR were: all-cause mortality 0.86 (95%CI 0.76-0.98, p trend=0.01); nonfatal CVD and stroke, the OR was 0.84 (95%CI 0.70-0.99, p trend=0.04) and 0.69 (95%CI 0.51-0.93, p trend=0.02), respectively; and the OR for fracture was 0.70 (95%CI 0.54-0.92, p trend=0.004).

Porosity in Men With Fractures

Sundh D, Mellstrom D, Nilsson M, Karlsson M, Ohlsson C, Lorentzon M. Increased cortical porosity in older men with fracture. J Bone Miner Res 2015;30:1692-700.

Sundh et al reported that in 456 men, mean age 80.2 y, 87 (19.1%) had fractures at or after age 50 y, 52 (11.4%) had a fracture before the baseline exam and 35 (7.7%) had had an X-ray verified fracture between baseline and 5-y follow-up. Men in the all-fracture group and in the X-ray verified group had higher porosity, by 15.8% vs. 11.4% and 21.6%, respectively, than men in the nonfracture group. Cortical porosity was associated with fracture (OR per SD increase 1.49) and with any X-ray verified fracture alone (OR 1.73). Including aBMD (spine or hip, respectively). Porosity was associated with any fracture (OR 1.54) and with X-ray verified fracture alone (OR 1.49) even after adjustment for aBMD.

Sex Hormone Changes During Ageing in Men

Hsu B, Cumming RG, Seibel MJ, Naganathan V, Blyth FM, Bleicher K, Dave A, Le Couteur DG, Waite LM, Handelsman DJ. Reproductive hormones and longitudinal change in bone mineral density and incident fracture risk in older men: The Concord Health and Aging in Men Project. J Bone Miner Res 2015;30:1701-8.

Hsu et al studied 1705 men aged >70 y at baseline (2 and 5 y). Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip. Serum SHBG (β=-0.071), FSH (β=-0.085), LH (β=-0.070), and E1 (β=0.107) remained associated with BMD loss in multivariate models. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. These variables may be biomarkers of bone health.

Serum Hormonal Binding Globulin and Fracture Risk in Men

Vandenput L, Mellstrom D, Kindmark A, Johansson H, Lorentzon M, Leung J, Redlund-Johnell I, Rosengren BE, Karlsson MK, Wang YX, Kwok T, Ohlsson C. High serum SHBG predicts incident vertebral fractures in elderly men. J Bone Miner Res 2015; doi:10.1002/jbmr.2718.

Vandenput et al reported incident clinical vertebral fractures (n=242 cases) in 4324 men during follow-up of 9.1 y. In a subsample (n=2256), spine X-rays were obtained at baseline and 4.3 y to identify incident radiographic vertebral fractures (n=157 cases). Neither serum estradiol nor testosterone predicted incident clinical vertebral fractures. High serum SHBG, however, was associated with increased clinical vertebral fracture risk (1.24, 1.12-1.37). SHBG was also associated with increased incident radiographic vertebral fracture risk (combined data set; OR per SD increase, 95% CI: 1.23, 1.05-1.44).

Osteocalcin and Glucose

Jung KY, Kim KM, Ku EJ, Kim YJ, Lee DH, Choi SH, Jang HC, Shin CS, Park KS, Lim S. Age- and sex-specific association of circulating osteocalcin with dynamic measures of glucose homeostasis. Osteoporos Int 2015; doi:10.1007/s00198-015-3315-7.

Jung et al conducted a cross-sectional analysis from 719 participants aged 20-85 y: men <50 y (n=131), men ≥50 y (n=191), women <50 y (n=108), and women ≥50 y (n=279). Insulin resistance (HOMA-IR) and β cell function (HOMA-β) from a 75-g oral glucose tolerance test was assessed. The serum osteocalcin was higher in women aged ≥50 y than women <50 y (20.4±7.8 vs. 17.9±6.8 ng/ml, p<0.001), but there was no difference between men by age. The participants diagnosed with diabetes had lower serum osteocalcin levels than normal or prediabetic participants. Multivariable regression analyses indicated that serum osteocalcin had a negative and independent association with HbA1c levels in men and women aged <50 y, but not in women ≥50 y.

PTH Treatment and Gap Junctions

Pacheco-Costa R, Davis HM, Sorenson C, Hon MC, Hassan I, Reginato RD, Allen MR, Bellido T, Plotkin LI. Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain. Bone 2015;81:632-43.

Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. Pacheco-Costa et al reported that in mice lacking the CT domain (Cx43DeltaCT/fl) had lower cancellous bone volume but higher cortical thickness than controls. PTH failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture in cortical bone in Cx43DeltaCT mice with or without osteocytic full length Cx43. Bone mass and bone formation markers were increased in all mouse models, regardless of whether full length or Cx43DeltaCT were or not expressed. Cx43 CT domain is involved in bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions.

Sclerostin Antibody Therapy in Glucocorticoid-induced Osteoporosis

Yao W, Dai W, Jiang L, Lay EY, Zhong Z, Ritchie RO, Li X, Ke H, Lane NE. Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int 2015; doi:10.1007/s00198-015-3308-6.

Yao et al evaluated the dose-dependent effects of glucocorticoids (GCs) (0, 0.8, 2.8, and 4 mg/kg/d) and Scl-Ab on autophagic osteoblasts, bone mass, and bone strength. GC treatment at 2.8 and 4 mg/kg/d of methylprednisolone lowered trabecular bone volume (Tb-BV/TV) at the lumbar vertebrae and distal femurs, cortical bone mass at the midshaft femur (FS), and cortical bone strength compared to placebo (PL). In mice treated with GC and Scl-Ab, Tb-BV/TV increased by 60-125 %, apparent bone strength of the lumbar vertebrae by 30-70 %, FS-BV by 10-18 %, and FS-apparent strength by 13-15%, as compared to GC vehicle-treated mice. GC treatment at 4 mg/kg/d reduced the number of autophagic osteoblasts by 70 % on the vertebral trabecular bone surface compared to the PL group (PL, GC 0 mg), and GC + Scl-Ab treatment.

Achiou Z, Toumi H, Touvier J, Boudenot A, Uzbekov R, Ominsky MS, Pallu S, Lespessailles E. Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia. Bone 2015;81:691-701.

Achiou et al studied male Wistar rats allocated to a control group (C) or one of 4 groups injected subcutaneously with methylprednisolone (5 mg/kg/d, 5 d/week) also given subcutaneously 2 d/week with vehicle (M) or Scl-Ab-VI (M+S: 25 mg/kg/d) and submitted or not to treadmill interval training exercise (1 h/d, 5 d/week) for 9 weeks (M+E, M+E+S). Methylprednisolone increased % fat mass and % apoptotic osteocytes, reduced whole body and femoral BMC, reduced femoral BMD and osteocyte lacunae occupancy. This effect was associated with lower trabecular bone volume (BV/TV) at the distal femur. Exercise increased BV/TV, osteocyte lacunae occupancy, while reducing fat mass, the bone resorption marker NTx, and osteocyte apoptosis. Exercise did not affect BMC or cortical microarchitecture. Scl-Ab increased osteocalcin and prevented the deleterious effects of M on bone mass, further increasing BMC, BMD and BV/TV to levels above the C group. Scl-Ab increased femoral cortical bone parameters at distal part and midshaft. Scl-Ab prevented the decrease in osteocyte lacunae occupancy and the increase in osteocyte apoptosis induced by M. The addition of exercise to Scl-Ab treatment did not result in additional improvements in bone mass or bone strength parameters.

Long-term Antiresorptive Therapy

Adler RA, Fuleihan GE, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R, Jr., Pignolo RJ, Sellmeyer DE. Managing osteoporosis in patients on long-term bisphosphonate treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2015; doi:10.1002/jbmr.2708.

Adler et al reported that in the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 y had fewer clinical vertebral fractures than those switched to placebo after 5 y. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 y. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, after 5 y of oral bisphosphonate (BP) or 3 y of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 y (oral) or 6 y (intravenous), with periodic evaluation, should be considered. For women not at high fracture risk after 3-5 y of BP treatment, a drug holiday of 2-3 y can be considered.

Bisphosphonate Treatment of Osteonecrosis of the Femoral Head

Yuan HF, Guo CA, Yan ZQ. The use of bisphosphonate in the treatment of osteonecrosis of the femoral head: A meta-analysis of randomized control trials. Osteoporos Int 2015; doi:10.1007/s00198-015-3317-5.

Yuan et al reported a meta-analysis of studies of treatment of osteonecrosis of the femoral head (ONFH). They examined only randomized control trials, progression to collapse, total hip arthroplasty (THA) incidence, and improvement of Harris hip score (HHS). Five eligible trials were identified involving 329 subjects with 920.9 patient-years of follow-up. The clinical outcomes were not improved by BP therapy (progression to collapse: risk ratio=0.71 (0.41, 1.24), p=0.23; THA incidence: risk ratio=0.61 (0.33, 1.15), p=0.13; HHS improvement: mean difference = 3.26 (-5.12, 11.64), p=0.45). The current analysis does not support the use of BPs for ONFH.

Figure 4. Clinical outcomes of progression to collapse (a), THA incidence (b), and HHS improvement (c) with bisphosphonate therapy when compared with placebo. Reproduced from Osteoporos Int 2015;doi:10.1007/s00198-015-3317-5 with permission from Springer.




Vitamin D and BMD

Jemielita TO, Leonard MB, Baker J, Sayed S, Zemel BS, Shults J, Herskovitz R, Denburg MR. Association of 25-hydroxyvitamin D with areal and volumetric measures of bone mineral density and parathyroid hormone: Impact of vitamin D-binding protein and its assays. Osteoporos Int 2015; doi:10.1007/s00198-015-3296-6.

Jemielita et al compared measures of vitamin D-binding protein (DBP) using a monoclonal vs. polyclonal ELISA in 304 adults (158 blacks, 146 whites), ages 21-80 y. Measures of DBP obtained using a monoclonal vs. polyclonal ELISA were not correlated (rs=0.02, p=0.76). Free and bioavailable 25(OH)D based on the polyclonal assay were lower in black than white participants (p<0.0001); this race difference was not evident using the monoclonal assay. Adjusted for age, sex, calcium intake, and race, all forms of 25(OH)D were negatively associated with PTH, but the absolute coefficient was greatest for total 25(OH)D (-0.34, p<0.001) versus free/bioavailable 25(OH)D (-0.18/-0.24 depending on DBP assay, p≤0.003). None of the measures of 25(OH)D were associated with BMD across DXA and pQCT sites.

Vitamin D and Muscle Strength

Cangussu LM, Nahas-Neto J, Orsatti CL, Bueloni-Dias FN, Nahas EA. Effect of vitamin D supplementation alone on muscle function in postmenopausal women: A randomized, double-blind, placebo-controlled clinical trial. Osteoporos Int 2015;26:2413-21.

Cangussu et al reported a double-blind, placebo-controlled clinical trial involving 160 Brazilian postmenopausal women randomized to vitamin D3 1000 IU/d orally (n=80) or placebo group (n=80). After 9 months, 25(OH)D from 15.0±7.5 to 27.5±10.4 ng/ml (+45.4 %) in the VITD group and decreased from 16.9±6.7 to 13.8±6.0 ng/ml (-18.5 %) in the placebo group (p<0.001). In the vitamn D group, there was an increase in muscle strength (+25.3 %) of the lower limbs (p=0.036). In women in the placebo group, there was loss (-6.8 %) in the lean mass (p=0.030).

Osteonecrosis of the Jaw

Zhang X, Hamadeh IS, Song S, Lesko LJ, Gong Y. Osteonecrosis of the jaw in the United States Food and Drug Administration's Adverse Event Reporting System (FAERS). J Bone Miner Res 2015; doi:10.1002/jbmr.2693

Zhang et al identified 17,119 cases of ONJ. ORs by therapy were: pamidronate (OR=498.9), zoledronate (OR=171.7), alendronate (OR=63.6). Denosumab had lower ORs than all BPs except for etidronate. In patients with cancer, the ORs for zoledronate and denosumab were 125.2 and 4.9, respectively. In patients with osteoporosis, the OR were 1.1 (1.0-1.18) for zoledronate and 0.63 (0.56-0.70) for denosumab. The intravenous BPs were associated with the highest risk for ONJ, RANKL inhibitor was associated with risk comparable to BPs used for osteoporosis such as etidronate, while the anti-angiogenic agents and m-TOR inhibitors were associated with the lowest risk for ONJ. The high risk for ONJ in zoledronate and denosumab was mainly observed in those treated for prevention of skeletal events. There was limited evidence risk in those treated for osteoporosis.

de Molon RS, Shimamoto H, Bezouglaia O, Pirih FQ, Dry SM, Kostenuik P, Boyce RW, Dwyer D, Aghaloo TL, Tetradis S. OPG-Fc but not zoledronic acid discontinuation reverses osteonecrosis of the jaws (ONJ) in mice. J Bone Miner Res 2015;30:1627-40.

de Molon et al treated mice with vehicle, zoledronic acid (ZA), or OPG-Fc for 11 weeks to induce ONJ. Antiresorptives were then discontinued for 6 or 10 weeks. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure; each resolved 10 weeks after discontinuing OPG-Fc, not ZA. Recovery of tartrate-resistant acid phosphatase-positive osteoclast numbers occurred after discontinuing OPG-Fc, not ZA.



Very reassuring findings

Supported by an unrestricted educational grant from