Normocalcaemic hyperparathyroidism and primary hyperparathyroidism: least significant change for adjusted serum calcium.

INTRODUCTION: The least significant change (LSC) is a term used in individuals in order to evaluate whether one measurement has changed significantly from the previous one. It is widely used when assessing bone mineral density (BMD) scans. To the best of our knowledge, there no such estimate available in the literature for patients with disorders of calcium metabolism. Our aim was to provide an estimate of the least significant change for albumin-adjusted calcium in patients with normocalcaemic hyperparathyroidism (NPHPT) and primary hyperparathyroidism (PHPT). METHODS: We used the within-subject standard deviatio calculated in a population of NPHPT and PHPT patients and multiplied it by 2.77. RESULTS: The LSC for NPHPT and PHPT were found to be 0.25 and 0.24 mmol/L, respectively (1.00 and 0.96 mg/dL). In clinical practice, the value of 0.25 mmol/L could be used. DISCUSSION: The least significant change given, could be used in two ways in these patients. First, it gives a range to which values are expected. This can provide some reassurance for the patient and the physician in cases of intermittent hypercalcaemia. Moreover, it can be a marker of whether an individual has an actual significant change of his calcium after parathyroid surgery.

The prevalence and natural history of normocalcaemic hypoparathyroidism in a United Kingdom referral population.

CONTEXT: Normocalcaemic hypoparathyroidism (NHYPO) is characterized by low levels of parathyroid hormone (PTH) with normal levels of calcium. There is little in the current literature on this disease, with only two studies published on its prevalence, while its natural history remains relatively unknown. OBJECTIVES: To identify the prevalence of NHYPO in a UK referral population and to study the natural history of the disorder. DESIGN: Retrospective study. Five-year follow-up. PATIENTS: 6280 patients referred for a BMD measurement in a Metabolic Bone referral centre. MEASUREMENTS: Prevalence of NHYPO and variability of calcium. RESULTS: Based on laboratory results on the index day, 22 patients with NHYPO were identified. Four patients were excluded due to non-PTH-induced hypocalcaemia and unconfirmed data. The final prevalence was 0.29%. Only 67% had persistent normocalcaemia, and the rest had intermittent hypocalcaemia. Two of these patients also had persistently low PTH on two occasions. Most of the patients had one PTH measurement available. No patient developed permanent hypoparathyroidism. CONCLUSIONS: The prevalence calculated from this UK referral population is lower when compared to results from previous studies. NHYPO patients often have episodes of hypocalcaemia with some cases having no apparent reason for calcium levels below the reference range.

Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History.

CONTEXT: Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive. OBJECTIVES: The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT). DESIGN: A retrospective study was conducted over 5 years. SETTING: The setting for this study was a metabolic bone referral center. PATIENTS: A total of 6280 patients were referred for a bone mineral density measurement (BMD). MAIN OUTCOME MEASURES: The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures. RESULTS: We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium. CONCLUSIONS: NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.

Balancing benefits and risks in the era of biologics.

Biologics are substances synthetized from biological sources used in the prevention and treatment of several diseases. Rheumatologists have many years of experience with biologics for the treatment of immune-mediated diseases and osteoporosis. Randomized clinical trials and postmarketing studies have demonstrated that treatment with biologics can result, albeit infrequently, in serious adverse events. To date, several risk mitigation strategies have been identified and implemented. The objective of the present perspective review is to examine the risk mitigation strategies of biologic treatments, with special focus on anti-tumor necrosis factors and denosumab.

Novel PLS3 variants in X-linked osteoporosis: Exploring bone material properties.

BACKGROUND: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation. DISCUSSION: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype. CONCLUSION: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation.

Effect of Teriparatide Treatment on Circulating Periostin and Its Relationship to Regulators of Bone Formation and BMD in Postmenopausal Women With Osteoporosis.

Context: Treatment of postmenopausal osteoporosis with teriparatide parathyroid hormone amino terminal 1-34 increases bone formation and improves bone microarchitecture. A possible modulator of action is periostin. In vitro experiments have shown that periostin might regulate osteoblast differentiation and bone formation through Wnt signaling. The effect of teriparatide on periostin is not currently known. Objectives: To determine the effect of teriparatide treatment on circulating levels of periostin and other regulators of bone formation and investigate how changes in periostin relate to changes in bone turnover markers, regulators of bone formation, and bone mineral density (BMD). Participants and Design: Twenty women with osteoporosis; a 2-year open-label single-arm study. Intervention: Teriparatide 20 µg was administered by subcutaneous injection daily for 104 weeks. Periostin, sclerostin, and Dickkopf-related protein 1, procollagen type I N-terminal propeptide (PINP), and C-telopeptide of type I collagen were measured in fasting serum collected at baseline (two visits) and then at weeks 1, 2, 4, 12, 26, 52, 78, and 104. BMD was measured at the lumbar spine, total hip, and femoral neck using dual energy x-ray absorptiometry. Results: Periostin levels increased by 6.6% [95% confidence interval (CI), -0.4 to 13.5] after 26 weeks of teriparatide treatment and significantly by 12.5% (95% CI, 3.3 to 21.0; P < 0.01) after 52 weeks. The change in periostin correlated positively with the change in the lumbar spine BMD at week 52 (r = 0.567; 95% CI, 0.137 to 0.817; P < 0.05) and femoral neck BMD at week 104 (r = 0.682; 95% CI, 0.261 to 0.885; P < 0.01). Conclusions: Teriparatide therapy increases periostin secretion; it is unclear whether this increase mediates the effect of the drug on bone.

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.

Supine vs decubitus lateral patient positioning in vertebral fracture assessment.

In vertebral fracture assessment (VFA), lateral scans are obtained with the patient positioned supine (C-arm densitometers) or lateral decubitus (fixed-arm densitometers). We aimed to determine the impact of positioning on image quality and fracture definition. We performed supine and decubitus lateral VFA in 50 postmenopausal women and used the algorithm-based qualitative method to identify vertebral fractures. We compared the 2 techniques for the identification of fractures (kappa analysis) and compared the numbers of unreadable vertebrae (indiscernible endplates) and vertebrae that were projected obliquely (Wilcoxon matched-pairs signed-rank test). The kappa score for agreement between the VFA techniques (to identify women with vertebral fractures) was 0.84 (95% confidence interval [CI]: 0.68-0.99), and for agreement with fracture assessments made from radiographs, kappa was 0.76 (95% CI: 0.57-0.94) for both supine and decubitus lateral VFA. There were more unreadable vertebrae with supine lateral (48 vertebrae in supine lateral compared with 14 in decubitus lateral; p=0.001), but oblique projection was less common (93 vertebrae compared with 145 in decubitus lateral; p=0.002). We conclude that there were significantly different projection effects with supine and decubitus lateral VFA, but these differences did not influence the identification of vertebral fractures in our study sample.

Performance of quantitative ultrasound measurements of bone for monitoring raloxifene therapy.

Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy.

Depot medroxyprogesterone acetate use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.

OBJECTIVE: To ascertain whether increased bone turnover in depot medroxyprogesterone acetate (DMPA) users after peak bone mass is associated with bone mineral loss. DESIGN: Three-year, observational, longitudinal study. SETTING: General practice and family planning clinics. PATIENT(S): Women over age 34: established DMPA users (n = 23), discontinuers (n = 14), and controls (n = 27). MAIN OUTCOME MEASURE(S): Change in spine and hip bone mineral density (BMD). RESULT(S): Despite increased biochemical markers of bone turnover in DMPA users, there was no decrease in BMD. Bone turnover markers did not correlate with change in BMD. CONCLUSION(S): In established DMPA users, after peak bone mass, a single normal BMD measurement could provide reassurance for long-term use. Measurement of bone turnover does not predict bone loss in DMPA users.

Use of DXA-based structural engineering models of the proximal femur to discriminate hip fracture.

Several DXA-based structural engineering models (SEMs) of the proximal femur have been developed to estimate stress caused by sideway falls. Their usefulness in discriminating hip fracture has not yet been established and we therefore evaluated these models. The hip DXA scans of 51 postmenopausal women with hip fracture (30 femoral neck, 17 trochanteric, and 4 unspecified) and 153 age-, height-, and weight-matched controls were reanalyzed using a special version of Hologic's software that produced a pixel-by-pixel BMD map. For each map, a curved-beam, a curved composite-beam, and a finite element model were generated to calculate stress within the bone when falling sideways. An index of fracture risk (IFR) was defined over the femoral neck, trochanter, and total hip as the stress divided by the yield stress at each pixel and averaged over the regions of interest. Hip structure analysis (HSA) was also performed using Hologic APEX analysis software. Hip BMD and almost all parameters derived from HSA and SEM were discriminators of hip fracture on their own because their ORs were significantly >1. Because of the high correlation of total hip BMD to HSA and SEM-derived parameters, only the bone width discriminated hip fracture independently from total hip BMD. Judged by the area under the receiver operating characteristics curve, the trochanteric IFR derived from the finite element model was significant better than total hip BMD alone and similar to the total hip BMD plus bone width in discriminating all hip fracture and femoral neck fracture. No index was better than total hip BMD for discriminating trochanteric fractures. In conclusion, the finite element model has the potential to replace hip BMD in discriminating hip fractures.

Effects of Depot medroxyprogesterone acetate on bone density and bone metabolism before and after peak bone mass: a case-control study.

INTRODUCTION: Depot medroxyprogesterone acetate (DMPA; Depo-Provera, Tadworth, UK) contraception is used by more than 9 million women worldwide and has a high usage among teenagers in the United Kingdom and the United States. Previous studies have found that DMPA use is associated with a bone density deficit. OBJECTIVES: This case-control matched study aims to eliminate potential confounding factors, identify whether the effect of DMPA on the skeleton is age specific, and determine the effects of DMPA on hormones and bone turnover. DESIGN/PARTICIPANTS: We measured bone density, bone turnover, and hormones in individually matched case-control pairs of women: 50 pairs aged 18-25 yr and 50 pairs aged 35-45 yr. RESULTS: DMPA use was associated with a 5% bone density deficit at the lumbar spine and hip in women who started DMPA use before age 20 yr but not after age 34 yr. Bone turnover was increased in DMPA users in both age groups. DMPA users had lower estradiol and higher IGF-I than controls, and younger DMPA users had higher dehydroepiandrosterone sulfate than controls. In a multiple regression model, estradiol and IGF-I were associated with bone turnover, but addition of DMPA to the model made the association with estradiol nonsignificant. CONCLUSIONS: DMPA use is associated with a bone density deficit at the spine and hip when used before peak bone mass. DMPA acts on the skeleton mainly through estrogen deficiency.

Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women.

UNLABELLED: Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population-based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip. INTRODUCTION: Many risk factors predict fractures overall, but it is less clear whether certain factors relate to vertebral fractures in particular. The aim of this study was to compare the risk factors for vertebral and nonvertebral fractures. MATERIALS AND METHODS: We carried out a 10-yr prospective population-based study of 375 women who were 50-85 yr of age initially. At baseline, we measured BMD, blood and urine biochemistry, and anthropometric measurements. Medical and lifestyle data were obtained by questionnaire. Incident vertebral fractures were determined for 311 subjects from spinal radiographs at 0, 2, 5, 7, and 10 yr using an algorithm-based qualitative method, and nonvertebral fractures were confirmed radiographically. Relative risks were calculated by Cox regression analysis. RESULTS: During follow-up, 70 subjects sustained one or more nonvertebral fractures and 29 sustained one or more vertebral fractures. Risk factors that predicted both types of fracture included increasing age, decreasing BMD at all sites, prevalent vertebral fracture, and shorter estrogen exposure. For nonvertebral fractures only, the risk factors included low urinary creatinine and less frequent use of stairs. The factors for vertebral fractures included lighter weight, reduced body fat, heavy smoking, lower serum calcium, albumin, and thyroid T(3), weak grip strength, and poor physical capability. In a multivariate model, weight, fat mass, serum calcium and T(3), prevalent vertebral fracture, and physical capability remained significant. Furthermore, grip strength, serum albumin, weight loss, and physical capability were associated with rate of bone loss at the femoral neck, and a fast rate of bone loss was also associated with vertebral fractures. CONCLUSIONS: We conclude that overall frailty, which may consist of general poor health, small or thin body size, and lack of strength and physical capability, predicts vertebral fractures but is not a significant predictor of nonvertebral fractures. Bone loss rates are associated with similar risk factors and also with the incidence of vertebral fractures.

Comparison of densitometric and radiographic vertebral fracture assessment using the algorithm-based qualitative (ABQ) method in postmenopausal women at low and high risk of fracture.

UNLABELLED: Using ABQ diagnosis, the sensitivity to detect VF of densitometric versus radiographic assessment in 755 postmenopausal women was 71-81% and specificity was 97%. Misdiagnosis was influenced by image quality and was more common for mild deformities. INTRODUCTION: Using densitometric vertebral fracture assessment (VFA), prevalent fractures are identified when vertebral height appears reduced by >or=20%. However, this approach does not discriminate between osteoporotic vertebral fracture (VF) and nonosteoporotic deformity, which increases the false-positive rate. Algorithm-based qualitative diagnosis (ABQ) focuses on vertebral endplate fracture to exclude these deformities but has not been applied in VFA. We wished to determine whether densitometric image quality is adequate for ABQ assessment. Our aims were to (1) calculate agreement between VFA and radiography using ABQ to identify prevalent VF and (2) identify the primary reasons for any discordant diagnosis. METHODS: Radiographic and densitometric spine images for postmenopausal women at low risk (LR; n = 459) and high risk (HR; n = 298) of VF were assessed using ABQ. Agreement between imaging modalities for VF diagnosis was assessed by kappa statistics using ABQ radiographic readings as the gold standard. RESULTS: The prevalence of VF was 11-29% (radiography) and 9-26% (VFA) in the LR and HR groups, respectively. Agreement between imaging modalities was good or very good (kappa = 0.62-0.81 in the LR and HR populations). The sensitivity to detect women with VF by VFA was 71% and 84% in the LR and HR populations, respectively, and specificity was 97%. Fifty-two (77%) and 60 (61%) of vertebrae misclassified by VFA in the LR and HR populations were mild fractures and 37 (54%) and 62 (63%) were wedge fractures. One third of fractures missed by VFA were related to poor or unreadable image quality (n = 27 and 28 vertebrae in the LR and HR populations, respectively). CONCLUSIONS: There was good agreement between VFA and radiography using ABQ to identify prevalent VF in women at LR or HR of osteoporotic VF. Vertebrae misclassified by VFA were primarily mild fractures or deformities, and two thirds of all fractures missed by VFA were related to poor or unreadable image quality.

The discriminative ability of peripheral and axial bone measurements to identify proximal femoral, vertebral, distal forearm and proximal humeral fractures: a case control study.

Previous studies evaluating peripheral bone measurement devices have often used discontinued technologies, compared single devices, only evaluated a single fracture syndrome or failed to make a comparison with central densitometry, which is currently the gold standard for fracture discrimination. We have used a case control study to evaluate the ability of different peripheral and central bone techniques to discriminate between fracture cases and controls, determine the impact of different measurement sites, evaluate the role of measuring the cortical or trabecular envelopes using quantitative computed tomography (QCT) and determine the impact of using combinations of sites and techniques on fracture discrimination. We recruited postmenopausal women with proximal femoral (n=53), vertebral (n=73), distal forearm (n=78) or proximal humeral (n=75) fractures, and 500 population-based women (age 55-80 years). All subjects had measurements of the spine, total hip and distal forearm with dual-energy X-ray absorptiometry (DXA), distal forearm QCT and quantitative ultrasound (QUS) of the heel (four devices), finger (two devices), radius and metatarsal. The association of each device with fracture was expressed as the age-adjusted standardized odds ratios (sOR) per 1-SD decrease of population variance. The association of bone measurements with fracture was site-specific. We found the hip (sOR up to 3.40) and vertebral (sOR up to 4.67) fractures were more closely associated with central bone measurements than upper limb fractures (sOR 1.96 and 2.05). The performance of heel broadband ultrasound attenuation (sOR 2.09-2.41), heel speed of sound (sOR 1.79-2.28) and peripheral BMD (sOR 2.07 and 2.24) was comparable with total hip (sOR 2.46) and lumbar spine DXA (sOR 2.31) in discriminating all types of osteoporotic fracture. In general, measuring cortical or trabecular envelopes did not increase sOR. However, combining different measurement sites or technologies provided additional information, which was independent of total hip BMD. The ability of different bone measurements to discriminate between fracture cases and controls is device- and site-specific, with additional information obtained by combining measurement sites and technologies.

Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial.

In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar (P = 0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.

The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial.

Long-term adherence and persistence with any therapy are very poor ( approximately 50%). Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed medication. We examined whether monitoring by nursing staff could enhance adherence and persistence with antiresorptive therapy and whether presenting information on response to therapy provided additional benefit. In addition we evaluated the impact of monitoring on treatment efficacy. Seventy-five postmenopausal women with osteopenia were randomized to 1) no monitoring, 2) nurse-monitoring, or 3) marker-monitoring. All subjects were prescribed raloxifene. At 12, 24, and 36 wk, the nursing staff reviewed subjects in the monitored (nurse-monitoring or marker-monitoring) groups using a predefined protocol. The marker-monitored group were also presented a graph of response to therapy using percentage change in urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, at each visit. Biological response to therapy at 1 yr was determined using the percent change in bone mineral density (BMD) and uNTX. Treatment adherence and persistence were assessed using electronic monitoring devices. Survival analysis showed that the monitored group increased cumulative adherence to therapy by 57% compared with no monitoring (P = 0.04). There was a trend for the monitored group to persist with therapy for 25% longer compared with no monitoring (P = 0.07). Marker measurements did not improve adherence or persistence to therapy compared with nurse-monitoring alone. Adherence at 1 yr was correlated with percent change in hip (BMD) (r = 0.28; P = 0.01) and percent change in uNTX (r = -0.36; P = 0.002). In conclusion, monitoring of patients increased adherence to therapy by 57% at 1 yr. Increased adherence to therapy increased the effectiveness of raloxifene therapy determined using surrogate end points.

Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review.

Deleterious effect of oral corticosteroids on bone has been well documented, whereas this remains debated for inhaled ones (ICS). Our objectives were to analyze the effects of ICS on bone mineral density, fracture risk and bone markers. We performed an exhaustive systematic research of all controlled trials potentially containing pertinent data, peer-reviewed by a dedicated WHO expert group, and comprehensive meta-analyses of the data. Inclusion criteria were ICS, and BMD/markers/fractures in asthma/chronic obstructive pulmonary diseases (COPD) and healthy patients. Analyses were performed in a conservative fashion using professional dedicated softwares and stratified by outcome, study design and ICS type. Results were expressed as standardized mean difference/effect size (ES), relative risk (RR) or odds ratio (OR), depending on study design and outcome units. Publication bias was investigated. Twenty-three trials were reviewed; 11 papers fit the inclusion criteria and were assessed for the main analysis. Quality scores for the randomized controlled trials (RCTs) were 80%, 71% for the prospective cohort studies, and 78% for the retrospective cohort and cross-sectional studies. We globally assessed ICS effects on BMD and found deleterious effects: ES=0.61 ( p=0.001) for healthy subjects, and ES=0.27 ( p<0.001) for asthma/COPD patients. For these patients, this effect was 0.21 ( p<0.01) at the lumbar spine, and 0.26 ( p<0.001) at the hip or femoral neck. A single study evaluated the impact of ICS on hip fracture and reported an increased OR of 1.6 (1.24; 2.03). Lumbar fracture rate differences did not reach the level of statistical significance: 1.87 (0.5; 6.94). Osteocalcin and PICP were decreased and ICTP, pyridinoline and deoxypyridinoline levels were not significantly affected. Budesonide (BUD) appeared to be the ICS inducing the less deleterious effects on bone, followed by beclomethasone dipropionate (BDP) and triamcinolone (TRI). Publication bias investigation provided non-significant results. In our meta-analyses, BUD at a mean daily dose (SD) of 686 microg (158 microg), BDP at 703 microg (123 microg) and TRI at 1,000 microg (282 microg) were found to affect bone mineral density and markers in patients suffering from the two major respiratory diseases. These findings could have practical implication in the long-term management of asthmatic and COPD patients.