Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Diffuse osteosclerosis as a presentation of recurrent breast cancer: role of endothelin 1.

We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. INTRODUCTION: Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. METHODS: Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. RESULTS: The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. CONCLUSIONS: Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.

Can vitamin D metabolite measurements facilitate a "treat-to-target" paradigm to guide vitamin D supplementation?

UNLABELLED: Substantial variability exists in the serum 25(OH)D increase observed in response to vitamin D supplementation. Measurement of circulating cholecalciferol and 24,25(OH)2D, as indicators of vitamin D absorption and degradation, respectively, account for approximately half of the variation in serum 25(OH)D observed following supplementation. INTRODUCTION: Vitamin D supplementation produces a variable response in serum 25(OH)D. This variability likely reflects, in part, differences in vitamin D absorption and/or degradation. Despite this variation in response, virtually all expert recommendations endorse a fixed vitamin D supplementation dose, an approach also used in most prospective studies. Such utilization of a single vitamin D dose does not assure attaining any pre-specified target 25(OH)D level, thereby compromising clinical care and prospective supplementation trials. This study begins addressing this weakness by exploring the feasibility of vitamin D metabolite measurements to predict serum 25(OH)D level attained following supplementation. METHODS: Ninety-one community-dwelling postmenopausal women with baseline 25(OH)D of 10-30 ng/mL received oral vitamin D3, 2300 or 2500 IU, daily for 4-6 months. Serum 25(OH)D, cholecalciferol (D3), and 24,25(OH)2D were measured before and at the end of supplementation to determine if metabolite concentrations allow prediction of the 25(OH)D level attained. RESULTS: From baseline and follow-up data, we derived a multiple linear regression model predicting posttreatment 25(OH)D as follows: final 25(OH)D = 8.3 + (1.05*initial 25(OH)D) - (7.7*initial 24,25(OH)2D) + (0.53*final D3) + (4.2*final 24,25(OH)2D). This model has an adjusted R(2) = 0.55, thus accounting for approximately half of the observed variance in the final 25(OH)D level. CONCLUSIONS: The contributions of circulating cholecalciferol and 24,25(OH)2D to this predictive model can be considered as indicators of intestinal absorption and clearance, respectively. This paradigm requires further study; it may allow efficient "treat-to-25(OH)D-target" strategies useful in optimizing prospective studies and clinical practice.

What analytic method should clinicians use to derive spine T-scores and predict incident fractures in men? Results from the MrOS study.

UNLABELLED: In this study, the area under the curve was highest when using the lowest vertebral body T-score to diagnose osteoporosis. In men for whom hip imaging is not possible, the lowest vertebral body T-score improves the ability to diagnose osteoporosis in men who are likely to have an incident fragility fracture. INTRODUCTION: Spine T-scores have limited ability to predict fragility fracture. We hypothesized that using lowest vertebral body T-score to diagnose osteoporosis would better predict fracture. METHODS: Among men enrolled in the Osteoporotic Fractures in Men Study, we identified cases with incident clinical fracture (n = 484) and controls without fracture (n = 1,516). We analyzed the lumbar spine bone mineral density (BMD) in cases and controls (n = 2,000) to record the L1-L4 (referent), the lowest vertebral body, and International Society for Clinical Densitometry (ISCD)-determined T-scores using a male normative database and the L1-L4 T-score using a female normative database. We compared the ability of method to diagnose osteoporosis and, therefore, to predict incident clinical fragility fracture, using area under the receiver operator curves (AUCs) and the net reclassification index (NCI) as measures of diagnostic accuracy. ISCD-determined T-scores were determined in only 60 % of participants (n = 1,205). RESULTS: Among 1,205 men, the AUC to predict incident clinical fracture was 0.546 for L1-L4 male, 0.542 for the L1-L4 female, 0.585 for lowest vertebral body, and 0.559 for ISCD-determined T-score. The lowest vertebral body AUC was the only method significantly different from the referent method (p = 0.002). Likewise, a diagnosis of osteoporosis based on the lowest vertebral body T-score demonstrated a significantly better net reclassification index (NRI) than the referent method (net NRI +0.077, p = 0.005). By contrast, the net NRI for other methods of analysis did not differ from the referent method. CONCLUSION: Our study suggests that in men, the lowest vertebral body T-score is an acceptable method by which to estimate fracture risk.

Adjustment for body mass index and calcitrophic hormone levels improves the diagnostic accuracy of the spot urine calcium-to-creatinine ratio.

SUMMARY: Providers diagnose hypercalciuria using a 24-hour or random urine samples. We compared calcium measurements from paired 24-hour and morning urine samples; measurements correlated poorly. We developed a formula to correct random urine calcium levels. Corrected levels showed excellent agreement with 24-hour measurements. Until validation, providers should diagnose hypercalciuria using 24-hour tests. INTRODUCTION: Hypercalciuria is a risk factor for osteoporosis and nephrolithiasis. The 24-hour urine calcium (24HUC) measurement is the gold standard to diagnose hypercalciuria, but the spot urine calcium-to-creatinine ratio (SUCCR) is more convenient. Although authors claim they are interchangeable, we observed inconsistencies during the conduct of a clinical trial. Therefore, we systematically evaluated agreement between the tests. METHODS: During a 28-inpatient calcium absorption studies in 16 postmenopausal women, we simultaneously collected paired fasting morning and 24-hour urine specimens. RESULTS: We found moderate correlation between paired SUCCR and 24HUC specimens (r = 0.57, p = 0.002), but the SUCCR underestimated 24HUC by a mean of 83 mg (Bland-Altman). We diagnosed hypercalciuria (24HUC >250 mg) in eight specimens using the 24HUC, but only in two specimens using the SUCCR (25% sensitivity). We developed a regression model to predict 24HUC using SUCCR, parathyroid hormone, body mass index, and 1,25(OH)(2)D. The model improved diagnostic sensitivity to 100% and decreased Bland-Altman bias of the SUCCR to +0.06 mg/kg/24-hour. CONCLUSIONS: We conclude that the SUCCR underestimates urine calcium loss and does not reliably diagnose hypercalciuria. A formula derived from multivariate regression incorporating other readily measurable variables greatly improved the SUCCR's accuracy. Future studies must verify this correction before clinical implementation.

"Evidence-based" or "logic-based" medicine?

Low trauma fractures are the cardinal manifestation of osteoporosis. Their occurrence supersedes bone mineral density in deciding whether specific therapy is warranted. We therefore disagree with the notion that a densitometric threshold for treatment should be applied to patients over age 50 who suffer low trauma distal radius fracture.

Increased Young's modulus and hardness of Col1a2oim dentin.

Mice harboring the Col1a2(oim) mutation (oim) express dentinogenesis imperfecta. To determine the effect of Col1a2 genotype on tissue mechanical properties, we compared Young's modulus and hardness of dentin in the 3 Col1a2 genotypes. Upper incisors were tested by nanoindentation. Genotype had a significant effect on Young's modulus, but there was not a simple mutant allele dosage relationship. The effect of genotype on hardness did not reach significance. Hardness and Young's modulus were greater near the dento-enamel junction than near the pulp chamber. Greater hardness and Young's modulus values near the dento-enamel junction reflected continued mineralization of the dentin following its initial synthesis. Analysis showed the mechanical data to be consistent with Fourier transform infrared and backscattered electron microscopy studies that revealed increased mineralization in oim bone. Analysis of the data suggests that clinical fragility of teeth in oim mice is not due to deficiencies of hardness or Young's modulus, but may be due to defects in post-yield behavior or resistance to fatigue damage.

A linkage map of mouse chromosome 12: localization of Igh and effects of sex and interference on recombination.

Inheritance of restriction fragment length polymorphisms associated with four anonymous DNA markers (D12Nyu1, 2, 3 and 4), the Fos proto-oncogene, the Mtv-9 viral integration site, and the alpha 1-antitrypsin (Aat-1) and immunoglobulin heavy chain (Igh) gene families in the mouse has been followed in a backcross experiment. A Bayesian multilocus map-building strategy yielded the map: centromere-D12Nyu2-10 cM-D12Nyu1-2 cM-D12Nyu3-15 cM-Fos-1 cM-D12Nyu4-2 cM-Mtv-9-8 cM-Aat-1-17 cM-Igh-C. A map constructed from male meiotic data was substantially shorter than one constructed from female meiotic data. Significant interference was observed for the linkage group. Two groups of markers studied in recombinant inbred strains of mice could be interpolated into the map: Es-25, D12Nyu10, D12Nyu7 and Apob form a cluster proximal to D12Nyu2, and Ly-18, Ah, and D12Nyu5 form a cluster between D12Nyu2 and D12Nyu1. These data establish an unambiguously ordered linkage group including Igh and Aat-1 that spans most of chromosome 12.

Possible derivation of the laboratory mouse genome from multiple wild Mus species.

Laboratory strains of mice are thought to be derived from wild populations of Mus domesticus. Many instances of non-domesticus genetic information fixed in these strains have been described, however, and the amount of strain-to-strain genetic variation exceeds that found in wild domesticus populations. In order to estimate the extent of the non-domesticus contribution to laboratory mouse genomes, and to determine whether it could account for observed variation, we have used computer simulations to investigate the properties of genetically marked chromosomal segments and the distribution of residual allogenicity at various times during inbreeding. A locus or chromosomal segment is allogenic if it is unfixed within a lineage at a given time. The odds of fixation of a foreign chromosome segment are predicted to be an exponentially decreasing function of its length. The median segment length is predicted to be 17 centimorgans. Available data for markers of chromosomes 1, 9 and 12 in recombinant inbred strain sets conform to these predictions. Together, the results suggest that introgression of non-domesticus chromosomes and segregation of residual allogenicity are sufficient to account for the genetic diversity observed among inbred mouse strains and substrains.

Bone strength and related traits in HcB/Dem recombinant congenic mice.

Fracture susceptibility depends jointly on bone mineral content (BMC), gross bone anatomy, and bone microarchitecture and quality. Overall, it has been estimated that 50-70% of bone strength is determined genetically. Because of the difficulty of performing studies of the genetics of bone strength in humans, we have used the HcB/Dem series of recombinant congenic (RC) mice to investigate this phenotype. We performed a comprehensive phenotypic analysis of the HcB/Dem strains including morphological analysis of long bones, measurement of ash percentage, and biomechanical testing. Body mass, ash percentage, and moment of inertia each correlated moderately but imperfectly with biomechanical performance. Several chromosome regions, on chromosomes 1, 2, 8, 10, 11, and 12, show sufficient evidence of linkage to warrant closer examination in further crosses. These studies support the view that mineral content, diaphyseal diameter, and additional nonmineral material properties contributing to overall bone strength are controlled by distinct sets of genes. Moreover, the mapping data are consistent with the existence of pleiotropic loci for bone strength-related phenotypes. These findings show the importance of factors other than mineral content in determining skeletal performance and that these factors can be dissected genetically.

Vitamin C-sulfate inhibits mineralization in chondrocyte cultures: a caveat.

Differentiating chick limb-bud mesenchymal cell micro-mass cultures routinely mineralize in the presence of 10% fetal calf serum, antibiotics, 4 mM inorganic phosphate (or 2.5 mM beta-glycerophosphate), 0.3 mg/ml glutamine and either 25 microg/ml vitamin C or 5-12 microg/ml vitamin C-sulfate. The failure of these cultures to produce a mineralized matrix (assessed by electron microscopy, 45Ca uptake and Fourier transform infrared microscopy) led to the evaluation of each of these additives. We report here that the "stable" vitamin C-sulfate (ascorbic acid-2-sulfate) causes increased sulfate incorporation into the cartilage matrix. Furthermore, the release of sulfate from the vitamin C derivative appears to be responsible for the inhibition of mineral deposition, as demonstrated in cultures with equimolar amounts of vitamin C and sodium sulfate.

Synteny-defined candidate genes for congenital and idiopathic scoliosis.

Idiopathic scoliosis (IS) is a common but poorly understood syndrome. Congenital scoliosis (CS) is less common but comparably unexplored. Previous studies suggest that each has a significant genetic component. However, the occurrence of scoliosis in the presence of other hereditary connective tissue syndromes raises the possibility that IS and CS are in fact a heterogeneous group of disorders with varied pathogenetic mechanisms. Mouse mutations have proven informative in identifying genes that are important in the development of the musculoskeletal system and provided important mechanistic insights regarding their roles in human disease. We sought to identify candidate genes for human IS and CS by reviewing mouse mutations with phenotypes affecting the axial skeleton. We performed a systematic review using the Mouse Genome Database (MGD), the Genome Database (GDB), and the Online Mendelian Inheritance in Man (OMIM) world-wide-web sites with additional searches performed based on the results of this initial search. We identified approximately 400 mouse mutations, reviewed approximately 250 of these for vertebral phenotypes, assessed 45 of these for synteny conservation between mouse and man, and identified 28 mouse mutations for which 29 credible candidates for human scoliosis could be identified based on mouse phenotypic and mapping data. For each of these, we have synthesized information about the mouse mutant phenotype, mapping data, information regarding molecular pathogenesis when a specific causative gene has been identified, and information regarding plausible candidates based on map position when the causative gene has not been identified. Among these were three loci for which the mutant gene had been identified and the human homologue was known. Some of the mouse mutants have phenotypes similar to human syndromes.

Linkage, association, and the genetic analysis of bone mineral density and related phenotypes: an overview for clinicians.

Most medical genetic studies seek to answer one of two questions: What genes are important in determining disease risk? and What alleles of a candidate gene confer excess risk? This article seeks to provide physicians with a practical approach to assessing articles on genetic topics, using examples from bone mineral density and related areas. First, this article reviews the essential features of meiosis, crossing over, and allele detection. Second, mapping strategies are described and illustrated. Third, this article considers studies of the association between alleles of specific candidate genes and bone phenotypes. Linkage without association and association without linkage are both possible. Fourth, the ability of studies using inbred mice to establish both linkage and association is explained. Fifth, the transmission disequilibrium test is proposed as a superior design for investigating the association of alleles with bone phenotypes. Sixth and last, a systematic approach to reading medical genetic studies critically is developed. Common shortcomings in published articles include insufficient evidence for candidate choice, confusion between functionally significant alleles and markers, and failure to distinguish between identity by descent and identity by state.

A review of clinical trials of therapies for osteoporosis using fracture as an end point.

As the population ages, fragility fractures grow in importance as a public health problem. The principal goal of osteoporosis therapy is primary and secondary fracture prevention. A growing choice of therapies is now available for the treatment of osteoporosis. In this article, we review their efficacy using fracture prevention as an end point. The considerable heterogeneity among studies with regard to patient age, past fracture history, fracture site, and analytical methods precludes the possibility of performing a meaningful meta-analysis. Fracture outcomes have been reported in clinical trials with calcium supplementation, vitamin D supplementation, estrogen replacement therapy (ERT), calcitonin, etidronate, alendronate, sodium fluoride (NaF), parathyroid hormone (PTH), and raloxifene. Compelling evidence for fracture prevention has been provided for calcium and vitamin D supplementation and alendronate treatment. Evidence of fracture prevention exists for ERT, raloxifene, calcitonin, etidronate, and PTH. Data on NaF are inconsistent. Across agents, there is a trend toward greater efficacy for patients at greatest risk of fracture.

Clinical, genetic and environmental factors associated with congenital vertebral malformations.

Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an example in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations.

Patient variables impact lumbar spine dual energy X-ray absorptiometry precision.

INTRODUCTION: Changes in bone mineral density are used to monitor osteoporosis therapy. To determine whether a change in bone mass is clinically significant, the precision of bone mineral density measurements must be known. METHODS: We therefore measured the impact of vertebral body exclusion on dual energy X-ray absorptiometry (DXA) precision. At one university and one Veterans Affairs DXA center, three radiology technologists each scanned 30 participants twice, with repositioning between scans, to estimate DXA precision. Three International Society for Clinical Densitometry-certified physicians reviewed all lumbar spinal scans to note the presence of focal structural defects. We calculated precision for subsets of vertebrae, and for virtual samples of patients with and without physician-identified vertebral focal structural defects. We graphed the reciprocal of least significant change versus bone area to determine the dependence of precision on interpreted scan area. RESULTS: Within each sample, greater interpretable bone area improved precision. The contribution of interpreted bone area to precision differed among the samples, ranging from 57 to 94%. Greater population bone mineral density heterogeneity and presence of focal structural defects each decreased precision. CONCLUSION: All bone densitometry centers must determine precision using a sample representative of their served populations. Failure to do so may lead to incorrect determination of least significant change. Population heterogeneity, vertebral body exclusion and presence of focal structural defects each decreases precision.