Overview, Vol 13, Issue 12

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

"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.

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Calcium and Vitamin D
from the ASBMR 2013

Several meta-analyses and some studies suggest that calcium supplements increase the risk of hip fracture and cardiovascular events, while vitamin D supplementation increases fracture risk. These studies and studies that claim a benefit of calcium and vitamin D supplementation have flaws in design and execution such as treatment of individuals that were not deficient in either nutrient, large numbers of dropouts, poor compliance, and post hoc analyses. However, the lesson is clear; inferences regarding the efficacy of calcium and vitamin D supplementation must await trials that are well designed and executed. The trials need to evaluate safety as well as efficacy. Even a small increase in risk for adverse events may produce net harm, particularly when large segments of the population at low risk for fracture are supplemented.

Several meta-analyses and re-analyses of several studies were presented at the ASBMR addressing the potentially deleterious effects of calcium on cardiovascular outcomes and overall, no increase in risk was observed. Fracture risk reduction was observed but the benefit was small. There are more meta-analyses and remeta-analyses than trials. We will not know whether supplementation does net good, net harm or does nothing until the definition of ‘deficiency’ is rigorously established. Will this ever happen? Well, given the prevailing view that conducting a trial with a calcium group taking under 200-300 mg daily with a 25(OH)D level of less than 30 nmol/L is unethical, it is hard to envisage a change in the prevailing uncertainty.

Frost et al (1) identified 9 primary RCTs examining the efficacy of Ca+D on fracture risk and 3 post hoc analyses of RCT concerning the association between Ca+D and cardiovascular disease (CVD) outcomes. The investigators used the Bayesian approach to estimate the probability that supplements increased or decreased the risk of an outcome by more than 10%. Ca+D supplementation was associated with an 11% lower fracture risk (RR 0.89; 95% CI 0.80-0.97), a 10% lower nonvertebral fracture risk (RR 0.90; 0.79-0.99), a 14% reduction in clinical vertebral fracture (RR 0.86; 0.75-0.99), but no significant reduction in hip fracture risk (RR 0.88; 0.71-1.06). There was 48% chance that supplements reduced fracture risk by at least 10%. Supplements were not significantly associated with myocardial infarction (RR 1.18; 0.73-1.74), stroke (RR 1.17; 0.75-1.70), myocardial infarction or stroke (RR 1.14; 0.74-1.64), or death (RR 1.01; 0.67-1.58). The number needed to treat to reduce a fracture was 85, and the number needed to incur a CVD event was 170; a benefit/risk ratio of 2.

Ebeling et al (2) assessed calcium intake using a food frequency questionnaire in 407 men and women followed for 17.7 (1.1) years with a mean (SD) baseline age of 53 (5.4) years or who 103 (29.8%) had 172 prevalent vertebral deformities while 229 (66.2%) did not. The OR for vertebral fracture was 0.46 (95% CI 0.27-0.78) in those with a median energy-adjusted calcium intake of 1076 mg/d compared with those with an intake of 641 mg/d. The OR was 0.31 (95% CI 0.12-0.78) for severe vertebral fractures with a high intake. Associations with nonvertebral and hip fractures were not reported, presumably because no association was detected. These odds ratios are similar, or greater, than seen with potent remodeling suppressants or anabolic agents – a surprising observation given calcium supplements have only modest effects in reducing remodeling rate. Observational studies such as this never test causation, only association and to infer that a risk reduction of 54-69% reported in this study is actually due to the higher calcium intake is courageous.

Bauer et al (3) report that among 5967 men (74±6 yr), calcium intake was 1142±590 mg/d; 65% used calcium supplements. During 10 years 2022 men died; 687 due to CVD. Compared to the highest quartile (1565 mg/d), those in the lowest quartile for calcium intake (621 mg/d) had higher total mortality (RH=1.19, CI 1.02-1.39) before, but not after adjustment - total (RH=1.06, CI 0.96-1.18), cardiovascular mortality (RH=1.00, CI  0.83-1.20).

Lewis et al (4) undertook a meta-analysis of trials of calcium supplementation ± vitamin D and identified 19 studies fitting predefined criteria. The 4646 deaths in 59,844 participants yielded a RR of 0.96 (0.91-1.02), P=0.18 for those randomized to supplements. RR for the 3334 ischemic heart disease events in 46,843 participants was 1.02 (0.96-1.09), P=0.53 (I2=0%) while the RR for the 1097 myocardial infarction events in 49,048 participants was 1.09 (0.89-1.33), P=0.21. The data do not support that calcium supplementation ± vitamin D increase the risk of ischemic heart disease or total mortality in elderly women.

Prachi et al (5) suggest that the threshold for decreased calcium absorption occurs at a very low serum 25(OH)D level, 5 ng/ml. This inference was based on a study of 198 Caucasian and African American women (ages 25-45 years) randomized double blind to 400, 800, 1600, 2400 IU vitamin D3 or placebo for 12 months. Calcium intake was 1200-1400 mg/d. 128 women completed the study. Mean baseline serum 25(OH)D was 14.6 ng/ml (39 nmol/L) in Caucasians and 11.6 ng/ml in African Americans. Mean serum 25(OH)D increased to 40 ng/ml. There was no increase in calcium absorption with any dose of vitamin D. Baseline serum 25(OH)D of 20 ng/ml was divided into 5 ng/ml increments. There was no difference in absorption or in serum 1,25(OH)2D amongst the groups. Vitamin D did not increase calcium absorption up to a dose of 2400 IU daily or mean serum 25OHD of 41 ng/ml. No threshold level of serum 25(OH)D for calcium absorption was found at baseline or in the longitudinal study.

Radford et al (6) report followup of the Auckland calcium study, a 5-year randomised controlled trial of 1 g/d calcium citrate in 1471 postmenopausal women. Approximately 5 years post-trial, the authors collected information on 1408 participants alive at trial completion, they contacted 1174 women by phone and measured BMD at 10 years in 194 women who took medication for 5 years in the original trial. There was no effect on total fracture (HR 0.90, 95 % CI 0.75-1.07) or hip fracture incidence (1.40, 0.89-2.21), but reductions in forearm (0.62, 0.43-0.89) and vertebral fractures (0.52, 0.32-0.85) in those assigned to calcium. There were no between-group differences in BMD at 10 years. The adverse cardiovascular outcomes observed in the 5-year trial did not persist post-trial. Calcium supplementation for 5 years had no effect on total fracture incidence at 10 years. The positive benefits on BMD and the adverse cardiovascular effects did not persist once supplements were stopped.


Vitamin D and BMD
Much ado about not much

Despite uncertainties regarding the benefits and risks of vitamin D supplementation, there is widespread use of vitamin D in the community. This study is well worth reading, especially the erudite iconoclastic discussion. Reid et al (7) investigated whether vitamin D supplementation affects bone mineral density by including all randomized trials comparing interventions that differed only in vitamin D content. Of 3930 citations identified by the search strategy, 23 studies (mean duration 23.5 months, comprising 4082 participants, 92% women, average age 59 years) met the inclusion criteria. Mean baseline serum 25(OH)D was less than 50 nmol/L in 8 studies (n=1791). In 10 studies (n=2294), individuals were given vitamin D doses <800 IU/d. BMD was measured at one to five sites in each study, so 70 tests of significance were done. There were six findings of benefit, two of detriment, and the rest were nonsignificant. One study showed benefit at more than one site. A small benefit at the femoral neck was seen (weighted mean difference 0.8%, 95% CI 0.2-1.4). No effect at any other site was reported, including the total hip. There was a bias toward positive results at the femoral neck and total hip. Continuing widespread use of vitamin D for osteoporosis prevention is difficult to justify.


Insights into Bisphosphonate Action
from the ASBMR 2013

Ebetino et al (8) report that the influence on bone remodeling of nitrogen-containing bisphosphonates (N-BPs) depends on the affinity of the drug to mineral and its potency in inhibiting farnesyl diphosphate synthase (FPPS) of osteoclasts and their precursors. Prolonged residence in bone is likely to be related to the high bone affinity. For a given potency in inhibiting FPPS, lower affinity for mineral may result in wider distribution in bone matrix enabling access to remodeling sites but shorter matrix residence time may reduce efficacy but produce less concern about potential long-term skeletal side effects.

The effects may be region specific. Trabecular bone has a high surface area and a low matrix volume formed by its thin platelike architectural configuration – this design may allow adequate access and distribution of highly bound drug to remodeling sites and so efficacious suppression of remodeling of trabecular bone but the same drug may be less efficacious in cortical bone because it is bound tightly to subendosteal matrix and fail to access peri-Haversian remodeling effectively.

The authors improved the profile of N-BPs by optimizing their inhibition of the FPPS enzyme while reducing matrix affinity. Among the many analogs made, OX-14 (1-fluoro-2-(imidazo-[1,2-a]pyridin-3-yl)-ethyl-bisphosphonic acid) had of high inhibitory potency on FPPS with low affinity for mineralized matrix. OX-14 (IC50=2.5 nM), was a more potent inhibitor of FPPS than zoledronate (IC50=4.1 nM). Urinary excretion after parenteral administration was greater than other N-BPs in rats, indicating lower retention. With ibandronate as a control=1.0, the relative 24-h urinary excretion of alendronate, zoledronic acid, risedronate, OX-14 was 0.53, 0.61, 1.0, and 1.24 respectively. In assays of inhibition of bone resorption in vivo, OX-14 (D20=0.0003 mg P/kg) was more potent than alendronate D20=0.0016 mg P/kg; ibandronate D20=0.0006 mg P/kg and comparable to zoledronic acid D20=0.0001 mg P/kg (D20= the dose producing a 20% increase in BMD above vehicle). In a model of collagen-induced arthritis in rats, OX-14 demonstrated efficacy similar to other potent N-BPs. In the knee, a 0.5 mg P/kg dose of OX-14 decreased resorption by 100%, as did zoledronic acid, while no dose tested of alendronate was completely antiresorptive. Since these lower bone affinity BPs, at maximally effective doses, may reduce turnover more globally, these potent new FPPS inhibitors may also offer enhanced therapeutic utility in other bone related diseases.

An example of the differing effects of bisphosohonates (BPs) at cortical and trabecular sites was published by Smith et al (9) a decade ago. This paper is well worth reading, the authors discuss this aspect of accessibility in some detail. The relevant information in this paper is summarized in Figure 1.

Figure 1. Suppression of remodeling upon the trabecular and endocortical surface relative to controls was observed using ibandronate, but Haversian canal remodeling was not suppressed significantly, presumably due to failure to access the remodeling occurring within the cortical compartment. The concentration of ibandronate was higher in extracts of trabecular bone than cortical bone. Adapted from Bone, 31:45-55, Copyright (2003), with permission from Elsevier.


Greater Suppression of Intracortical Remodeling by Denosumab than by Alendronate

Another illustration of the importance of access to intracortical remodeling can be seen in the study by Zebaze et al (10), who report greater reduction in cortical porosity by denosumab than alendronate. The investigators randomized postmenopausal women, mean age 61 years, to placebo (n=82), alendronate 70 mg weekly (n=82), or denosumab 60 mg every 6 months (n=83) for 12 months. Denosumab reduced remodeling more rapidly and completely than alendronate, reduced porosity of the compact-appearing cortex (CC), outer and inner cortical transitional zones (OTZ, ITZ), at 6 months, more so by 12 months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12 months were [mean (95% CI)]; CC: -1.26% (-1.61, -0.91) vs. -0.48% (-0.96, 0.00), p=0.012; OTZ: -1.97% (-2.37, -1.56) vs. -0.81% (-1.45, -0.17), p=0.003; and ITZ: -1.17% (-1.38, -0.97) vs. -0.78% (-1.04, -0.52), p=0.021. Alendronate reduced porosity of the three cortical regions at 6 months relative to baseline and controls but further decreased porosity of the ITZ only at 12 months (Figure 2). By 12 months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6 months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) vs. 0.19% (0.13, 0.30), p=0.208.

Figure 2. The top image shows three-dimensional reconstruction of the distal radius with the compact-appearing cortex (green), outer (white) and inner (red) transitional zone, and trabecular compartment (yellow). Middle images show each of the regions segmented and reconstructed and the graphs show the corresponding changes in porosity and trabecular bone volume fraction at 0, 6, and 12 months in controls, alendronate, and denosumab-treated subjects. p<0.05 compared with abaseline, bmonth 6, ccontrol, and dalendronate. White dashed line: control; red line: alendronate; green line: denosumab. Reproduced from Bone, 59:173-9, Copyright (2014), with permission from Elsevier.


Atypical Fractures
Studies presented at the ASBMR 2013

Wang et al (11) followed 522,287 new BP users from their index prescription to diagnosis of subtrochanteric/femur shaft (n=948) or typical hip (n=9382) fracture. There were dose-dependent increases in incidences of subtrochanteric/femur shaft fractures with greater adherence. The age-adjusted rate (per 100,000 person years) of subtrochanteric/femur shaft fractures increased from 56.7 in the first year to 175.1 in the fifth year, compared with less compliant (from 44.3 to 66.6); a hazard ratio for compliant vs. less compliant of 1.23 (1.06-1.43) overall, 1.09 (0.89-1.34) before and 2.09 (1.48-2.95) after 3 years. Age-adjusted incidence of typical hip fractures was lower among compliant than less compliant (e.g., 873.8 vs. 1168.7 after 4 years, p<0.03).

Morin et al (12) hypothesized that patients with atypical femoral fracture (AFF) have geometrical variations of their lower limb so that tensile forces laterally are high. The authors compared the geometrical parameters in 25 subjects with AFF with duration of BP use of 10.6 SD [4.6] yrs. There were 40 AFF. Compared to women with diaphyseal fractures (n=11), those with subtrochanteric fractures (n=5) had a lesser femur neck-shaft angle (123.0° SD [3.3] vs. 129.2° SD [7.1]; p<0.05), longer femoral offset (4.2 SD [0.2] cm vs. 3.7 SD [0.6] cm; p<0.05), and less bowing in frontal plane (- 2.7° SD [5.6] cm vs. -4.2° SD [3.3]; NS).

Adams et al (13) compared 115 patients with an AFF and 107 patients with other subtrochanteric/diaphyseal fractures (subtroch group), and 115 patients with ‘classic’ femoral neck or intertrochanteric hip fractures (hip group). Compared to the subtroch group, AFF cases were younger, more likely to be Asian, to have osteoporosis and to use BPs (OR 6.4; 95% CI 3.0-13.4). AFF cases also used BPs for longer (median 6.6 vs. 2.0 years, p<0.01), with risk increasing from OR 5.8 (95% CI 1.9-17.2) for 4 years use to OR 13.3 (95% CI 4.2-42.2) for use >8 years. Compared to the hip group, younger age, Asian race, osteoporosis, active use of BPs at index (OR 6.8; 95% CI 3.2-14.2), and longer duration of use of BPs were independent predictors of AFF status. AFF risk increased from OR 3.3 (95% CI 1.3-8.8) for 4 years BP use to 10.5 (95% CI 3.6-30.8) for >8 years use (p for trend<0.01).

Martelli et al (14) tested the hypothesis that AFF is associated with high cyclic tensile strains. The authors computed femur tensile strain distribution during walking in 10 postmenopausal women. A musculoskeletal model was scaled using anthropometry. The joint net moments were calculated using body motion and ground reaction forces during gait. Finite element analyses were performed applying muscle and hip reaction forces and using a full constraint condition distally. Five phases of walking including heel-strike (A), the first (B) and the second (D) peak of the hip reaction force, midstance (C) and toe-off (E) were studied. Peak tensile strains corresponded with the two peaks. For each peak, high tensile strains were found on the lateral femur diaphysis. The maximum tensile strain was 0.4%, corresponding with the second peak of the hip reaction force (4.5 bodyweight). AFFs may be initiated in subregions subjected to high cyclic tensile strains where microcracks may progress.


ONJ and Altered Material Composition

Olejnik et al (15) report bone sequesters from 24 patients with ONJ following a BP treatment have altered material composition. BP-exposed bone sequesters have increased mineral to organic ratio (+12%) and a decrease of relative proteoglycan content (-35%), and a decrease of crystallinity (-2%) and mineral maturation (-41%) compared to healthy bones. These modifications were observed in benign-BP and malignant-BP groups. In addition, a shift of the phosphate ν1 band was highlighted by PLS-DA between bones control and BP-exposed bone sequesters, revealing a disruption of the apatitic phosphate environment in the jaw bone sequesters. Jaw bone quality is altered with an overmineralization and ultrastructural modifications of apatitic mineral in bone sequesters of BP-related ONJ.


Coffee is OK

Hallstrom et al (16) report that in a cohort of 61,433 women born in 1914-1948, follow-up from 1987-2008 identified 14,738 women having any fracture and 3871 had a hip fracture. In 5022, bone density was measured and osteoporosis observed in 1012. After multivariable adjustment, there was no evidence of a higher rate of any fracture (hazard ratio per 200 mL coffee = 0.99; 0.98, 1.00) or hip fracture (HR 0.97, 0.95, 1.00) with increasing coffee consumption. A high coffee intake (≥4 cups daily) vs. a low intake (<1 cup daily) was associated with a 2-4% lower bone density (P<0.001), but the odds ratio for osteoporosis was 1.28 (0.88, 1.87). Thus, high coffee consumption was associated with a small reduction in bone density that did not translate into an increased risk of fracture.


Declining Initiation of Therapy

Wysowski et al (17) report ~21.3 million prescriptions for oral BPs were dispensed in U.S. retail pharmacies in 2002. This increased 46% to a peak of 31.0 million in 2007 and 2008, and declined by 53% in a 4-year period to 14.7 million in 2012. Sales data showed 66% increase from 2002-2007 and 51% decrease from 2007-2012. Intravenous BP sales grew 3.8-fold from 149.5 thousand packages in 2007 to 561.6 thousand in 2010, followed by a 22% decrease in 2012. Reasons for the decline need to be identified.


Coupling and the Reversal Phase of Bone Remodeling Cycle

Anderson et al (18) have written a timely and instructive review of the much neglected reversal phase of the bone remodeling cycle. Bone remodeling does not only have a resorptive followed by a formation phase. Coupling between the resorption and formation phases of the remodeling cycle is believed to occur during a reversal phase that was widely written about during the last century (yes, time flies) but since the 1970s, the reversal phase has been neglected. This is likely to be an important error of omission, much like failing to recognise the importance of the osteocyte and the importance of cortical bone.

As discussed by Anderson et al, the cells of the reversal phase prepare resorptive lacunae for bone formation. These ‘reversal’ cells cover >80% of the eroded surfaces, but their nature is not identified, and it is not known whether malfunction of these cells contributes to bone loss. In this review the authors report that reversal cells are immunoreactive for factors typically expressed by osteoblasts, but not for monocytic markers. A subpopulation of reversal cells showed several distinctive characteristics suggestive of an arrested physiological status. Their prevalence correlated with decreased trabecular bone volume and osteoid and osteoblast surfaces in postmenopausal osteoporosis. They were virtually absent in primary hyperparathyroidism in which the transition between resorption and formation occurs promptly. The authors suggest that arrested reversal cells reflect aborted remodeling cycles that did not progress to the bone formation. They propose that bone loss in postmenopausal osteoporosis does not only result from a failure of the volume of bone formed being less that the volume resorbed bone formed; bone loss may also be the result of failure of the reversal phase to initiate bone formation. This is not just a matter of semantics; if coupling is normal the imbalance in remodeling and bone loss may still occur due to mechanisms responsible for the birth, work and death of osteoclasts and osteoblasts. Abnormalities in coupling itself and the mechanisms responsible open an entirely new world of regulation, disregulation and therapeutic targets when this process is better defined and understand – the authors lead in this endeavor.

Figure 3. Histological appearance of reversal cells (Rv.Cs) in a biopsy from the iliac crest of patients with primary hyperparathyroidism. A and B: Masson’s trichrome stained cross sections of bone remodeling surfaces with osteoclasts (OCs), Rv.Cs on the reversal surface (Rv.Ss), and bone-forming osteoblasts (OBs) on OSs. The Rv.Ss were identified as eroded surfaces (ES) with broken lamella without OCs, but with mononucleated Rv.Cs. Rv.Cs appear elongated, but sometimes are more cuboidal when close to osteoid surface (OS, yellow arrows). Immunostaining (red) with the monocytic markers CD14 (C), CD68 (E), or CD163 (G) showed no immunoreactivity in the Runx2fl Rv.Cs (arrows, brown nuclei), whereas neighboring OCs were positive for CD68. Immunostaining with the osteoblastic markers, Runx2 (D), alkaline phosphatase (ALP; F), and CD56 (H), reveals immunoreactivity (brown staining) in Rv.Cs next to (black arrows) or below (red arrow) TRAcPfl OCs (red staining). Scale bars: 50 mm (AeH). Reprinted from Am J Pathol, Vol 183, Andersen TL et al., Understanding coupling between bone resorption and formation: are reversal cells the missing link?, Pages 235-45, Copyright (2013), with permission from Elsevier.


Does Odanacatib Produce Earlier Coupling and of Bone Formation by the BMU than Alendronate?

Jensen et al (19) make an attempt to examine the effects of drug therapy on the reversal phase of bone remodeling. The authors hypothesized that odanacatib modifies the nature of remodeling following the resorption phase. They suggest that odanacatib shortens the reversal phase during trabecular remodeling in vertebrae of estrogen-deficient rabbits. Odanacatib was suggested to shorten the reversal phase compared to alendronate and produced a faster initiation of osteoid deposition on the eroded surfaces, and higher osteoblast recruitment reflected by higher densities of mature bone forming osteoblasts and an increased subpopulation of cuboidal osteoblasts. An increase in the interface between osteoclasts and surrounding osteoblast lineage cells may favor the osteoclast-osteoblast interactions required for bone formation. Odanacatib, but not aledronate, resulted in shallower resorption lacunae, a geometry favoring bone stiffness.


Genetic Variance in Microstructure

Havill et al (20) examined right femurs from 101 baboons (74 females, 27 males; aged 7-33 years) from a single pedigree. Age and sex effects account for 9% (Ct.Po) to 21% (W.Th) of intracortical microstructural variation. After accounting for age and sex, 61-82% of trait variance was due to genetic effects for osteonal area (On.Ar) h2=0.79, p=0.002), %On.B (h2=0.82, p=0.003), and W.Th (h2=0.61, p=0.013). This corresponds to 48-75% of the total phenotypic variance. Population-level variation in cortical microstructure is influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.


References

1. Frost S, Nguyen N, Center J, et al. Calcium plus vitamin D supplementation: a meta-analysis of risk and benefit. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=d7619370-676b-409a-a... Accessed January 9, 2014.

2. Ebeling P, English D, Nowson C, et al. Long term effects of higher dietary calcium intake on vertebral fractures and severe abdominal aortic calcification in older Australians. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=300bc661-98b2-4677-8... Accessed January 9, 2014.

3. Bauer D, Harrison S, Cawthon P, et al. Dietary and supplemental calcium intake and the risk of mortality in older men: the MrOS study. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=127b3258-faf3-40b1-9... Accessed January 9, 2014.

4. Lewis J, Rejnmark L, Ivey K, et al. The cardiovascular safety of calcium supplementation with or without vitamin D in elderly women: a collaborative meta-analysis of published and unpublished trial level evidence from randomised controlled trials. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=cb39c171-4131-43df-a... Accessed January 9, 2014.

5. Prachi J, Gallagher JC, Smith L. Vitamin D supplementation on calcium absorption in young women. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=31c582bc-8d5d-4db8-a... Accessed January 9, 2014.

6. Radford LT, Bolland MJ, Mason B, et al. The Auckland calcium study: 5-year post-trial follow-up. Osteoporos Int 2014;25:297.

7. Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2013; doi: 10.1016/S0140-6736(13)61647-5.

8. Ebetino FH, Lundy M, Kwaasi AA, et al. The successful design of a novel highly potent nitrogen-containing bisphosphonate with lower bone affinity. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=2cc3cea2-af93-43fe-a... Accessed January 9, 2014.

9. Smith SY, Recker RR, Hannan M, et al. Intermittent intravenous administration of the bisphosphonate ibandronate prevents bone loss and maintains bone strength and quality in ovariectomized cynomolgus monkeys. Bone 2003;32:45.

10. Zebaze RM, Libanati C, Austin M, et al. Differing effects of denosumab and alendronate on cortical and trabecular bone. Bone 2014;59:173-9.

11. Wang J, Ward M, Bhattacharyya T, et al. Adherence to oral bisphosphonates and the risk of subtrochanteric or siaphyseal femur fractures among US Medicare beneficiaries with part D coverage. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=458b0ee3-d644-446d-8... Accessed January 9, 2014.

12. Morin S, Godbout B, Wall M, et al. Lower limb geometrical parameters in the pathogenesis of bisphosphonate-associated atypical femur fractures. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=390955e4-f288-4998-9... Accessed January 9, 2014.

13. Adams A, Xue F, Wang J, et al. Atypical femoral fracture risk factors: a population-based case-control study. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=395bca3c-290e-4666-9... Accessed January 9, 2014.

14. Martelli S, Pivonka P, Kersh M, et al. Atypical femoral fractures are associated with high cyclic tensile strain regions during walking. Available at http://www.asbmr.org/asbmr-2013-abstract-detail?aid=a816cde1-c98e-4b21-b... Accessed January 9, 2014.

15. Hallstrom H, Byberg L, Glynn A, et al. Long-term coffee consumption in relation to fracture risk and bone mineral density in women. Am J Epidemiol 2013;178:898.

16. Olejnik C, Falgayrac G, During A, et al. Molecular alterations of bone quality in sequesters of bisphosphonates-related osteonecrosis of the jaws. Osteoporos Int 2013; doi: 10.1007/s00198-013-2514-3.

17. Wysowski DK, Greene P. Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012. Bone 2013;57:423.

18. Andersen TL, Abdelgawad ME, Kristensen HB, et al. Understanding coupling between bone resorption and formation; are reversal cells the missing link? Am J Pathol 2013;183:235.

19. Jensen PR, Andersen TL, Pennypacker BL, Duong LT, Delaisse JM. The bone resorption inhibitors odanacatib and alendronate affect post-osteoclastic events differently in ovariectomized rabbits. Calcif Tissue Int 2013; doi: 10.1007/s00223-013-9800-0.

20. Havill LM, Allen MR, Harris JA, et al. Intracortical bone remodeling variation shows strong genetic effects. Calcif Tissue Int 2013;93:472.


Reviews

Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review
Eriksen EF, Diez-Perez A, Boonen S
Bone 2014;58:126

Adipocytes and the regulation of bone remodeling: a balancing act
Nuttall ME, Shah F, Singh V, Thomas-Porch C, Frazier T, Gimble JM
Calcif Tissue Int 2013;doi:10.1007/s00223-013-9807-6

Cellular complexity of the bone marrow hematopoietic stem cell niche
Calvi LM, Link DC
Calcif Tissue Int 2013;doi:10.1007/s00223-013-9805-8

A review of phosphate mineral nucleation in biology and geobiology
Omelon S, Ariganello M, Bonucci E, Grynpas M, Nanci A
Calcif Tissue Int 2013;93:382

Osteocytes: regulating the mineral reserves?
Arnett TR
J Bone Miner Res 2013;28:2433

Cancer-associated bone disease
Rizzoli R, Body JJ, Brandi ML et al. for the International Osteoporosis Foundation Committee of Scientific Advisors Working Group on Cancer-Induced Bone Disease
Osteoporos Int 2013;24:2929