Metabolic effects of pamidronate in patients with metastatic bone disease

We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridinoline and deoxypyridinoline. Reference values were defined by 20 healthy controls matched by age and sex. Pamidronate induced a profound fall in bone resorption with a maximal effect within the first month after therapy. Changes in urinary calcium levels were confounded by a rise of 100% in the parathyroid hormone levels. Before treatment, pyridinoline and deoxypyridinoline were increased in 70% of patients, while urinary calcium was increased in only 40% of them. Thirteen patients had a > or = 50% fall in deoxypyridinoline levels and were considered as biochemical responders. These patients had a mean reduction in pain score of about 30% of baseline levels, which was significantly higher than the seven non-biochemical responders. In conclusion, urinary calcium is not a precise marker of bone resorption. Deoxypyridinoline seems to be the most specific bone resorption marker in cancer patients. Biochemical responders have the most benefit from pamidronate in terms of pain relief. This suggests that patients may benefit from more potent or repeated infusions of bisphosphonates

Establishing reference intervals for bone turnover markers in healthy postmenopausal women in a nonfasting state.

In order to interpret bone turnover markers (BTMs), we need to establish healthy reference intervals. It is difficult to establish reference intervals for older women because they commonly suffer from diseases or take medications that affect bone turnover. The aims of this study were: (1) to identify diseases and drugs that have a substantial effect on BTMs; (2) to establish reference intervals for premenopausal and postmenopausal women; and (3) to examine the effects of other factors on BTMs in healthy postmenopausal women. We studied women aged 30-39 years (n=258) and women aged 55-79 years (n=2419) from a five-European centre population-based study. We obtained a nonfasting serum and second morning void urine samples at a single baseline visit. BTMs were measured using automated immunoassay analysers. BTMs were higher in patients with vitamin D deficiency and chronic kidney disease. Three or more BTMs were higher in women who were osteoporotic and at least two BTMs were lower in women who were oestrogen replete, taking osteoporosis treatments or having diseases known to affect bone turnover. These were used as exclusion criteria for selecting the populations for the reference intervals. The reference intervals for BTMs were higher in postmenopausal than premenopausal women. Levels of BTMs were not dependent on geographical location and increased with age

Personalised 3D Assessment of Trochanteric Soft Tissues Improves HIP Fracture Classification Accuracy

Passive soft tissues surrounding the trochanteric region attenuate fall impact forces and thereby control hip fracture risk. The degree of attenuation is related to Soft Tissue Thickness (STT). STT at the neutral hip impact orientation, estimated using a regression relation in body mass index (BMI), was previously shown to influence the current absolute risk of hip fracture (ARF0) and its fracture classification accuracy. The present study investigates whether fracture classification using ARF0 improves when STT is determined from the subject’s Computed-Tomography (CT) scans (i.e. personalised) in an orientation-specific (i.e. 3D) manner. STT is calculated as the shortest distance along any impact orientation between a semi-automatically segmented femur surface and an automatically segmented soft tissue/air boundary. For any subject, STT along any of the 33 impact orientations analysed always exceeds the value estimated using BMI. Accuracy of fracture classification using ARF0 improves when using personalised 3D STT estimates (AUC = 0.87) instead of the BMI-based STT estimate (AUC = 0.85). The improvement is smaller (AUC = 0.86) when orientation-specificity of CT-based STT is suppressed and is nil when personalisation is suppressed instead. Thus, fracture classification using ARF0 improves when CT is used to personalise STT estimates and improves further when, in addition, the estimates are orientation specific

Maternal pregnancy vitamin D supplementation increases offspring bone formation in response to mechanical loading : findings from a MAVIDOS trial sub-study

The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (Δ) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ΔCTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children

denosumab in postmenopausal women with osteoporosis and diabetes subgroup analysis of freedom and freedom extension

Abstract Purpose Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated. Methods Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated. Results Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07–0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00–3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [ 1 ]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group. Conclusion Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed

Raman Spectral Variation for Human Fingernails of Postmenopausal Women is Dependent on Fracture Risk and Osteoporosis Status

Patients diagnosed with osteoporosis have reported loss of fingernail resilience as the disease progresses. Keratin is the predominant protein in human nail tissue, and its structure has been postulated to be different in fingernails clipped from subjects who have sustained fragility fractures and those who have not, which may offer a window into the donor\u27s bone health. This study was designed to qualify these differences, which may lead to the development of a novel screening tool for fracture risk. Raman spectroscopy was used to measure the fingernails of 633 postmenopausal women who presented at six fracture clinics located across the UK and Ireland. The Raman signals from donor\u27s fingernails were compared between (1) fracture and nonfracture and (2) osteoporotic versus non-osteoporotic donors The data presented show differences in the protein changes observed for pervasive osteoporosis compared to a general increased risk of fragility fracture. For fracture risk, compositional changes falling into broad classes of amino acid residue (aliphatic, aromatic, acidic, amide and sulphurous) were observed, while a difference in disulphide bonding levels was reaffirmed. For pervasive osteoporosis, the disulphide mode suggested increasing disorder in disulphide bonding orientation. Fractures were associated with a transition from alpha helical secondary structure to random, while the pervasive osteoporosis cases were associated with a transition to beta sheet structure. General fracture risk is associated with a change in the structure and composition of the keratin protein. Osteoporosis is associated with different protein structural changes and an increase in free acid groups. Copyright © 2017 John Wiley & Sons, Ltd

Bilateral proximal tibia fracture

A bilateral fracture of the proximal tibia is rare in children. We describe a girl with a bilateral fracture just distal of the epiphyseal plate after minimal trauma

Changes in Cross-Sectional Area of Spinal Canal and Vertebral Body Under 2 Years of Teriparatide Treatment: Results from the EUROFORS Study

The treatment of osteoporotic patients with teriparatide is associated with a significant increase in bone formation and gain of bone mass. The purpose of this post hoc analysis was to determine if the cross-sectional area (CSA) of the spinal canal and the vertebral body is affected by teriparatide treatment. Narrowing of the spinal canal might represent a safety problem, while widening of the vertebral CSA might improve mechanical stability. High-resolution computed tomography (HRCT) scans of vertebra T12 were obtained at baseline and after 6, 12, and 24 months of teriparatide treatment (20 μg/day) from 44 postmenopausal women with established osteoporosis participating in the prospective, randomized EUROFORS study. The CSA of the spinal canal did not decrease but increased marginally by 0.9% (2.6 mm2) over 24 months (P < 0.001), with a range from −0.5% (−2 mm2) to 3.1% (+8 mm2). Even when analyzing the spinal CSA on a slice-by-slice basis, no clinically relevant narrowing of the spinal canal was observed. For vertebral bodies, the CSA increased by 0.7% (5.7 mm2) over 24 months (P < 0.001), with a range from −0.4% (–3 mm2) to 1.6% (+14 mm2). Our data do not provide evidence for safety concerns regarding spinal canal narrowing. On the other hand, the increases observed for vertebral CSA apparently also only minimally contribute to the mechanical strengthening of the vertebral body under teriparatide treatment