Skeletal response to treatment with teriparatide (TPD) after bisphosphonate in post-menopausal women with osteoporosis and a high prevalence of secondary risk factors in real-life setting of a metabolic bone clinic; effect of age and vitamin D status.

PURPOSE: Teriparatide (TPD) is a skeletal anabolic agent used in patients with severe post-menopausal osteoporosis (PMO) and steroid-induced osteoporosis who are at hish risk of fracture. Predictors of therapeutic response to teriparatide in real-life setting are not well characterised. We investigated potential factors associated with teriparatide response in post-menopausal women with established osteoporosis. METHODS: We carried out a retrospective survey of 48 women, aged 73.2 [7.5] years with severe osteoporosis and prevalent fractures treated with TPD according to the NICE criteria. BMD was measured at baseline, 6-12 and 18-24 months at the lumbar spine (LS), total hip (TH) and femoral neck (FN). Bone turnover markers, serum 25 (OH)vitamin D were determined at 3-12 and 12-24 months. RESULTS: BMD increased at 6-12 months (% change mean [SEM] 6.5 [1.1] p = 0.004) and 18-24 months (8.45 % [1.2] p<0.001) at the LS. A significant increase in BMD was observed at FN (3.1 [1.3] % p = 0.02). Changes in BMD at the TH was higher in patients younger than 73 years compared to older women (% change in BMD 4.13 [1.64] % v/s -1.7 [1.1] p = 0.007). Baseline 25 (OH) vitamin D correlated with change in P1NP at 3-12 months (r = 0.45 p = 0.049). CONCLUSIONS: TPD-induced changes in BMD at the TH appears may be dependent on age. Vitamin D status may influence the early anabolic effect to TPD. Our data suggest that these factors may be important considerations when initiating and optimising treatment with TPD, although further larger studies are needed to confirm these findings.

Changes in bone mineral density and bone turnover in patients on 'drug holiday' following bisphosphonate therapy: real-life clinic setting.

OBJECTIVES: Treatment discontinuation after long-term bisphosphonate (BP), termed a 'drug holiday', has been proposed to reduce the risk of BP-associated complications. The duration of treatment cessation remains unclear. Changes in bone mineral density (BMD), bone turnover markers (BTMs) and their relationship with FRAX were assessed to help determine the optimum length of a 'drug holiday'. METHODS: A retrospective analysis of 134 patients (13M, 121F) aged [mean (SD)] 68·4 (8·2) years who discontinued BPs after treatment for 5·9 (3·0) years for osteoporosis was undertaken. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and biochemical parameters including serum 25 (OH) vitamin D, bone turnover markers (plasma CTX, P1NP) and FRAX scores were determined at discontinuation, 12-18 months and 24-30 months off treatment. RESULTS: BMD decreased significantly at the LS [% change mean (SD): -0·94 (3·6), P = 0·008], TH [-1·4 (2·4), P < 0·001] and FN [-1·8 (4·4), P < 0·001] after treatment discontinuation for 12-18 months. In the subgroup who remained off treatment for 24-30 months, a progressive decline in BMD was seen at the TH and FN with total % decrease of -2·52 (3·5) and -2·7 (4·76), P < 0·001, respectively. CTX and P1NP increased significantly at 12-18 months after discontinuation [% change CTX: 95 (88), P < 0·001, P1NP: 88 (73), P < 0·001]. FRAX scores were significant predictors of % change in BMD at the FN (P < 0·05), independently of bone turnover and vitamin D status. In summary, our data show that following a 'drug holiday', the use of DEXA scans, BTMs and FRAX may help guide when to resume treatment.

Differences in regional bone metabolism at the spine and hip: a quantitative study using (18)F-fluoride positron emission tomography.

SUMMARY: This study showed that regional bone blood flow and (18)F-fluoride bone plasma clearance measured by positron emission tomography are three times lower at the hip than the lumbar spine. INTRODUCTION: Measurements of effective bone plasma flow (K (1)), bone plasma clearance (K ( i )) and standardised uptake values (SUV) using (18)F-fluoride positron emission tomography ((18)F-PET) provide a useful means of studying regional bone metabolism at different sites in the skeleton. This study compares the regional (18)F-fluoride kinetics and SUV at the hip and lumbar spine (LS). METHODS: Twelve healthy postmenopausal women with no history of metabolic bone disease apart from two with untreated osteoporosis were recruited. Each subject underwent 60-min dynamic (18)F-PET scans at the LS and proximal femur two weeks apart. K (1), K ( i ) and SUV were measured at the LS (mean of L(1)-L(4)), femoral neck (FN), total hip (TH) and femoral shaft (FS). Differences between sites were assessed using the nonparametric Kruskal-Wallis test with a Bonferroni correction for multiple comparisons. RESULTS: Values of K (1), K ( i ) and SUV at the FN, TH and FS were three times lower than at the LS (p = 0.003). Amongst the proximal femur sites, K ( i ) and SUV were lower at the FS compared with the FN and TH, and SUV was lower at the TH compared with the FN (all p < 0.05). The volume of distribution was lower at the TH and FS compared with the LS (p < 0.05). CONCLUSION: The lower values of K (1), K ( i ) and SUV at the hip suggest that lower bone blood flow in the proximal femur is an important factor explaining the principal reason for the differences in bone fluoride kinetics between the LS and hip sites.

A direct in vivo measurement of 99mTc-methylene diphosphonate protein binding.

Quantitative studies of the kinetics of 99mTc-methylene diphosphonate (99mTc-MDP) in metabolic and metastatic bone disease require the measurement of free tracer in plasma to derive the input function. We describe a simple method of determination of free 99mTc-MDP in vivo based on measurements of the ratio of the renal plasma clearances of total 99mTc-MDP and 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA). The method is based on evidence that free MDP is cleared through the kidneys by glomerular filtration. Measurements of the fraction of free 99mTc-MDP were made between 0 and 4 h after injection in 70 postmenopausal women enrolled in a study of the effect of hormone replacement therapy on the whole-skeleton plasma clearance of 99mTc-MDP (K(bone)). The glomerular filtration rate (GFR) was measured simultaneously from the plasma clearance of 51Cr-EDTA. The mean fractions (and SD) of free MDP measured were 0.757 (0.050), 0.663 (0.062), 0.550 (0.052) and 0.472 (0.053), respectively, at 17, 90, 150 and 210 min after injection. The results agreed closely with data using protein precipitation with trichloroacetic acid. Between 2 and 4 h after injection, the biological half-life of free 99mTc-MDP in plasma was 92 min, compared with 540 min for bound MDP. Highly significant relationships were found between the fraction of free MDP measured in each patient at each of the four time points and the total plasma clearance of free 99mTc-MDP (K(total)=GFR+K(bone)), such that a larger value of K(total) was associated with a smaller fraction of free MDP. Multivariate regression analysis confirmed that this relationship held individually for both GFR and K(bone). A strong inverse relationship was found between K(total) and the plasma concentration of free 99mTc-MDP, but a much weaker relationship with the bound MDP concentration, a finding that is consistent with the slow re-equilibration of bound MDP in the circulation. The results confirm that the fraction of free 99mTc-MDP varies with time and shows significant differences between individuals, which are dependent on GFR and K(bone) amongst other factors.