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The Bone & Joint Journal
Vol. 95-B, Issue 9 | Pages 1201 - 1203
1 Sep 2013
Tsukeoka T Tsuneizumi Y Lee TH

We performed a CT-based computer simulation study to determine how the relationship between any inbuilt posterior slope in the proximal tibial osteotomy and cutting jig rotational orientation errors affect tibial component alignment in total knee replacement. Four different posterior slopes (3°, 5°, 7° and 10°), each with a rotational error of 5°, 10°, 15°, 20°, 25° or 30°, were simulated. Tibial cutting block malalignment of 20° of external rotation can produce varus malalignment of 2.4° and 3.5° with a 7° and a 10° sloped cutting jig, respectively. Care must be taken in orientating the cutting jig in the sagittal plane when making a posterior sloped proximal tibial osteotomy in total knee replacement.

Cite this article: Bone Joint J 2013;95-B:1201–3.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 2 | Pages 198 - 204
1 Feb 2011
Pandit H Jenkins C Gill HS Barker K Dodd CAF Murray DW

This prospective study describes the outcome of the first 1000 phase 3 Oxford medial unicompartmental knee replacements (UKRs) implanted using a minimally invasive surgical approach for the recommended indications by two surgeons and followed up independently. The mean follow-up was 5.6 years (1 to 11) with 547 knees having a minimum follow-up of five years. At five years their mean Oxford knee score was 41.3 (sd 7.2), the mean American Knee Society Objective Score 86.4 (sd 13.4), mean American Knee Society Functional Score 86.1 (sd 16.6), mean Tegner activity score 2.8 (sd 1.1). For the entire cohort, the mean maximum flexion was 130° at the time of final review.

The incidence of implant-related re-operations was 2.9%; of these 29 re-operations two were revisions requiring revision knee replacement components with stems and wedges, 17 were conversions to a primary total knee replacement, six were open reductions for dislocation of the bearing, three were secondary lateral UKRs and one was revision of a tibial component. The most common reason for further surgical intervention was progression of arthritis in the lateral compartment (0.9%), followed by dislocation of the bearing (0.6%) and revision for unexplained pain (0.6%). If all implant-related re-operations are considered failures, the ten-year survival rate was 96% (95% confidence interval, 92.5 to 99.5). If only revisions requiring revision components are considered failures the ten-year survival rate is 99.8% (confidence interval 99 to 100).

This is the largest published series of UKRs implanted through a minimally invasive surgical approach and with ten-year survival data. The survival rates are similar to those obtained with a standard open approach whereas the function is better. This demonstrates the effectiveness and safety of a minimally invasive surgical approach for implanting the Oxford UKR.


The Bone & Joint Journal
Vol. 96-B, Issue 3 | Pages 345 - 349
1 Mar 2014
Liddle AD Pandit HG Jenkins C Lobenhoffer P Jackson WFM Dodd CAF Murray DW

The cementless Oxford unicompartmental knee replacement has been demonstrated to have superior fixation on radiographs and a similar early complication rate compared with the cemented version. However, a small number of cases have come to our attention where, after an apparently successful procedure, the tibial component subsides into a valgus position with an increased posterior slope, before becoming well-fixed. We present the clinical and radiological findings of these six patients and describe their natural history and the likely causes. Two underwent revision in the early post-operative period, and in four the implant stabilised and became well-fixed radiologically with a good functional outcome.

This situation appears to be avoidable by minor modifications to the operative technique, and it appears that it can be treated conservatively in most patients.

Cite this article: Bone Joint J 2014;96-B:345–9.


The Bone & Joint Journal
Vol. 96-B, Issue 8 | Pages 1052 - 1061
1 Aug 2014
Thienpont E Schwab PE Fennema P

We conducted a meta-analysis, including randomised controlled trials (RCTs) and cohort studies, to examine the effect of patient-specific instruments (PSI) on radiological outcomes after total knee replacement (TKR) including: mechanical axis alignment and malalignment of the femoral and tibial components in the coronal, sagittal and axial planes, at a threshold of > 3º from neutral. Relative risks (RR) for malalignment were determined for all studies and for RCTs and cohort studies separately.

Of 325 studies initially identified, 16 met the eligibility criteria, including eight RCTs and eight cohort studies. There was no significant difference in the likelihood of mechanical axis malalignment with PSI versus conventional TKR across all studies (RR = 0.84, p = 0.304), in the RCTs (RR = 1.14, p = 0.445) or in the cohort studies (RR = 0.70, p = 0.289). The results for the alignment of the tibial component were significantly worse using PSI TKR than conventional TKR in the coronal and sagittal planes (RR = 1.75, p = 0.028; and RR = 1.34, p = 0.019, respectively, on pooled analysis). PSI TKR showed a significant advantage over conventional TKR for alignment of the femoral component in the coronal plane (RR = 0.65, p = 0.028 on pooled analysis), but not in the sagittal plane (RR = 1.12, p = 0.437). Axial alignment of the tibial (p = 0.460) and femoral components (p = 0.127) was not significantly different.

We conclude that PSI does not improve the accuracy of alignment of the components in TKR compared with conventional instrumentation.

Cite this article: Bone Joint J 2014; 96-B:1052–61.


The Bone & Joint Journal
Vol. 95-B, Issue 11 | Pages 1497 - 1499
1 Nov 2013
Abram SGF Nicol F Hullin MG Spencer SJ

We reviewed the long-term clinical and radiological results of 63 uncemented Low Contact Stress (LCS) total knee replacements (TKRs) in 47 patients with rheumatoid arthritis. The mean age of the patients at the time of surgery was 69 years (53 to 81). At a mean follow-up of 22 years (20 to 25), 12 patients were alive (17 TKRs), 27 had died (36 TKRs), and eight (ten TKRs) were lost to follow-up.

Revision was necessary in seven patients (seven TKRs, 11.1%) at a mean of 12.1 years (0 to 19) after surgery. In the surviving ten patients who had not undergone revision (15 TKRs), the mean Oxford knee score was 30.2 (16 to 41) at a mean follow-up of 19.5 years (15 to 24.7) and mean active flexion was 105° (90° to 150°). The survival rate was 88.9% at 20 years (56 of 63) and the Kaplan–Meier survival estimate, without revision, was 80.2% (95% confidence interval 37 to 100) at 25 years.

Cite this article: Bone Joint J 2013;95-B:1497–9.


The Bone & Joint Journal
Vol. 95-B, Issue 11_Supple_A | Pages 74 - 76
1 Nov 2013
Kamath AF McAuliffe CL Gutsche JT Kosseim LM Hume EL Baldwin KD Kornfield Z Israelite CL

Patient safety is a critical issue in elective total joint replacement surgery. Identifying risk factors that might predict complications and intensive care unit (ICU) admission proves instrumental in reducing morbidity and mortality. The institution’s experience with risk stratification and pre-operative ICU triage has resulted in a reduction in unplanned ICU admissions and post-operative complications after total hip replacement. The application of the prediction tools to total knee replacement has proven less robust so far. This work also reviews areas for future research in patient safety and cost containment.

Cite this article: Bone Joint J 2013;95-B, Supple A:74–6.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 9 | Pages 1238 - 1244
1 Sep 2010
Nicoll D Rowley DI

This study used CT analysis to determine the rotational alignment of 39 painful and 26 painless fixed-bearing total knee replacements (TKRs) from a cohort of 740 NexGen Legacy posterior-stabilised and cruciate-retaining prostheses implanted between May 1996 and August 2003.

The mean rotation of the tibial component was 4.3° of internal rotation (25.4° internal to 13.9° external rotation) in the painful group and 2.2° of external rotation (8.5° internal to 18.2° external rotation) in the painfree group (p = 0.024). In the painful group 17 tibial components were internally rotated more than 9° compared with none in the painfree group (p < 0.001). Additionally, six femoral components in the painful group were internally rotated more than 6° compared with none in the painfree group (p = 0.017). External rotational errors were not found to be associated with pain.

Overall, 22 (56.4%) of the painful TKRs had internal rotational errors involving the femoral, the tibial or both components. It is estimated that at least 4.6% of all our TKRs have been implanted with significant internal rotational errors.


The Bone & Joint Journal
Vol. 96-B, Issue 4 | Pages 492 - 496
1 Apr 2014
Klatte TO Kendoff D Kamath AF Jonen V Rueger JM Frommelt L Gebauer M Gehrke T

Fungal peri-prosthetic infections of the knee and hip are rare but likely to result in devastating complications. In this study we evaluated the results of their management using a single-stage exchange technique. Between 2001 and 2011, 14 patients (ten hips, four knees) were treated for a peri-prosthetic fungal infection. One patient was excluded because revision surgery was not possible owing to a large acetabular defect. One patient developed a further infection two months post-operatively and was excluded from the analysis. Two patients died of unrelated causes.

After a mean of seven years (3 to 11) a total of ten patients were available for follow-up. One patient, undergoing revision replacement of the hip, had a post-operative dislocation. Another patient, undergoing revision replacement of the knee, developed a wound infection and required revision 29 months post-operatively following a peri-prosthetic femoral fracture.

The mean Harris hip score increased to 74 points (63 to 84; p < 0.02) in those undergoing revision replacement of the hip, and the mean Hospital for Special Surgery knee score increased to 75 points (70 to 80; p < 0.01) in those undergoing revision replacement of the knee.

A single-stage revision following fungal peri-prosthetic infection is feasible, with an acceptable rate of a satisfactory outcome.

Cite this article: Bone Joint J 2014;96-B:492–6.


Bone & Joint Research
Vol. 3, Issue 10 | Pages 289 - 296
1 Oct 2014
van IJsseldijk EA Harman MK Luetzner J Valstar ER Stoel BC Nelissen RGHH Kaptein BL

Introduction

Wear of polyethylene inserts plays an important role in failure of total knee replacement and can be monitored in vivo by measuring the minimum joint space width in anteroposterior radiographs. The objective of this retrospective cross-sectional study was to compare the accuracy and precision of a new model-based method with the conventional method by analysing the difference between the minimum joint space width measurements and the actual thickness of retrieved polyethylene tibial inserts.

Method

Before revision, the minimum joint space width values and their locations on the insert were measured in 15 fully weight-bearing radiographs. These measurements were compared with the actual minimum thickness values and locations of the retrieved tibial inserts after revision.


The Bone & Joint Journal
Vol. 96-B, Issue 8 | Pages 1111 - 1118
1 Aug 2014
van der Heijden L Mastboom MJL Dijkstra PDS van de Sande MAJ

We retrospectively reviewed 30 patients with a diffuse-type giant-cell tumour (Dt-GCT) (previously known as pigmented villonodular synovitis) around the knee in order to assess the influence of the type of surgery on the functional outcome and quality of life (QOL). Between 1980 and 2001, 15 of these tumours had been treated primarily at our tertiary referral centre and 15 had been referred from elsewhere with recurrent lesions.

The mean follow-up was 64 months (24 to 393). Functional outcome and QOL were assessed with range of movement and the Knee injury and Osteoarthritis Outcome Score (KOOS), the Musculoskeletal Tumour Society (MSTS) score, the Toronto Extremity Salvage Score (TESS) and the SF-36 questionnaire. There was recurrence in four of 14 patients treated initially by open synovectomy. Local control was achieved after a second operation in 13 of 14 (93%). Recurrence occurred in 15 of 16 patients treated initially by arthroscopic synovectomy. These patients underwent a mean of 1.8 arthroscopies (one to eight) before open synovectomy. This achieved local control in 8 of 15 (53%) after the first synovectomy and in 12 of 15 (80%) after two. The functional outcome and QOL of patients who had undergone primary arthroscopic synovectomy and its attendant subsequent surgical procedures were compared with those who had had a primary open synovectomy using the following measures: range of movement (114º versus 127º; p = 0.03); KOOS (48 versus 71; p = 0.003); MSTS (19 versus 24; p = 0.02); TESS (75 versus 86; p = 0.03); and SF-36 (62 versus 80; p = 0.01).

Those who had undergone open synovectomy needed fewer subsequent operations. Most patients who had been referred with a recurrence had undergone an initial arthroscopic synovectomy followed by multiple further synovectomies. At the final follow-up of eight years (2 to 32), these patients had impaired function and QOL compared with those who had undergone open synovectomy initially.

We conclude that the natural history of Dt-GCT in patients who are treated by arthroscopic synovectomy has an unfavourable outcome, and that primary open synovectomy should be undertaken to prevent recurrence or residual disease.

Cite this article: Bone Joint J 2014; 96-B:1111–18.


The Bone & Joint Journal
Vol. 96-B, Issue 5 | Pages 665 - 672
1 May 2014
Gaston CL Nakamura T Reddy K Abudu A Carter S Jeys L Tillman R Grimer R

Bone sarcomas are rare cancers and orthopaedic surgeons come across them infrequently, sometimes unexpectedly during surgical procedures. We investigated the outcomes of patients who underwent a surgical procedure where sarcomas were found unexpectedly and were subsequently referred to our unit for treatment. We identified 95 patients (44 intra-lesional excisions, 35 fracture fixations, 16 joint replacements) with mean age of 48 years (11 to 83); 60% were males (n = 57). Local recurrence arose in 40% who underwent limb salvage surgery versus 12% who had an amputation. Despite achieving local control, overall survival was worse for patients treated with amputation rather than limb salvage (54% vs 75% five-year survival). Factors that negatively influenced survival were invasive primary surgery (fracture fixation, joint replacement), a delay of greater than two months until referral to our oncology service, and high-grade tumours. Survival in these circumstances depends mostly on factors that are determined prior to definitive treatment by a tertiary orthopaedic oncology unit. Limb salvage in this group of patients is associated with a higher rate of inadequate marginal surgery and, consequently, higher local recurrence rates than amputation, but should still be attempted whenever possible, as local control is not the primary determinant of survival.

Cite this article: Bone Joint J 2014;96-B:665–72.


The Bone & Joint Journal
Vol. 96-B, Issue 8 | Pages 1005 - 1015
1 Aug 2014
Alshryda S Sukeik M Sarda P Blenkinsopp J Haddad FS Mason JM

Intravenous tranexamic acid (TXA) has been shown to be effective in reducing blood loss and the need for transfusion after joint replacement. Recently, there has been interest in applying it topically before the closure of surgical wounds. This has the advantages of ease of application, maximum concentration at the site of bleeding, minimising its systemic absorption and, consequently, concerns about possible side-effects.

We conducted a systematic review and meta-analysis which included 14 randomised controlled trials (11 in knee replacement, two in hip replacement and one in both) which investigated the effect of topical TXA on blood loss and rates of transfusion. Topical TXA significantly reduced the rate of blood transfusion (total knee replacement: risk ratio (RR) 4.51; 95% confidence interval (CI): 3.02 to 6.72; p < 0.001 (nine trials, I2 = 0%); total hip replacement: RR 2.56; 95% CI: 1.32 to 4.97, p = 0.004 (one trial)). The rate of thromboembolic events with topical TXA were similar to those found with a placebo. Indirect comparison of placebo-controlled trials of topical and intravenous TXA indicates that topical administration is superior to the intravenous route.

In conclusion, topical TXA is an effective and safe method of reducing the need for blood transfusion after total knee and hip replacement. Further research is required to find its optimum dose for topical use.

Cite this article: Bone Joint J 2014;96-B:1005–15.


Bone & Joint Research
Vol. 3, Issue 10 | Pages 297 - 304
1 Oct 2014
Fitch DA Sedacki K Yang Y

Objectives

This systematic review and meta-analysis was conducted to determine the mid- to long-term clinical outcomes for a medial-pivot total knee replacement (TKR) system. The objectives were to synthesise available survivorship, Knee Society Scores (KSS), and reasons for revision for this system.

Methods

A systematic search was conducted of two online databases to identify sources of survivorship, KSS, and reasons for revision. Survivorship results were compared with values in the National Joint Registry of England, Wales, and Northern Ireland (NJR).


Bone & Joint Research
Vol. 3, Issue 6 | Pages 175 - 182
1 Jun 2014
Berstock JR Beswick AD Lenguerrand E Whitehouse MR Blom AW

Total hip replacement causes a short-term increase in the risk of mortality. It is important to quantify this and to identify modifiable risk factors so that the risk of post-operative mortality can be minimised. We performed a systematic review and critical evaluation of the current literature on the topic. We identified 32 studies published over the last 10 years which provide either 30-day or 90-day mortality data. We estimate the pooled incidence of mortality during the first 30 and 90 days following hip replacement to be 0.30% (95% CI 0.22 to 0.38) and 0.65% (95% CI 0.50 to 0.81), respectively. We found strong evidence of a temporal trend towards reducing mortality rates despite increasingly co-morbid patients. The risk factors for early mortality most commonly identified are increasing age, male gender and co-morbid conditions, particularly cardiovascular disease. Cardiovascular complications appear to have overtaken fatal pulmonary emboli as the leading cause of death after hip replacement.

Cite this article: Bone Joint Res 2014;3:175–82


The Bone & Joint Journal
Vol. 96-B, Issue 1 | Pages 122 - 126
1 Jan 2014
Bloch BV Patel V Best AJ

Since the introduction of the National Institute for Health and Care Excellence (NICE) guidelines on thromboprophylaxis and the use of extended thromboprophylaxis with new oral agents, there have been reports of complications arising as a result of their use. We have looked at the incidence of wound complications after the introduction of dabigatran for thromboprophylaxis in our unit.

We investigated the rate of venous thromboembolism and wound leakage in 1728 patients undergoing primary joint replacement, both before and after the introduction of dabigatran, and following its subsequent withdrawal from our unit.

We found that the use of dabigatran led to a significant increase in post-operative wound leakage (20% with dabigatran, 5% with a multimodal regimen; p < 0.001), which also resulted in an increased duration of hospital stay. The rate of thromboembolism in patients receiving dabigatran was higher (1.3%) than in those receiving the multimodal thromboprophylaxis regimen, including low molecular weight heparin as an inpatient and the extended use of aspirin (0.3%, p = 0.047). We have ceased the use of dabigatran for thromboprophylaxis in these patients.

Cite this article: Bone Joint J 2014;96-B:122–6.


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 7 | Pages 879 - 884
1 Jul 2008
Porteous AJ Hassaballa MA Newman JH

We identified 148 patients who had undergone a revision total knee replacement using a single implant system between 1990 and 2000. Of these 18 patients had died, six had developed a peri-prosthetic fracture and ten had incomplete records or radiographs. This left 114 with prospectively-collected radiographs and Bristol knee scores available for study. The height of the joint line before and after revision total knee replacement was measured and classified as either restored to within 5 mm of the pre-operative height or elevated if it was positioned more than 5 mm above the pre-operative height. The joint line was elevated in 41 knees (36%) and restored in 73 (64%).

Revision surgery significantly improved the mean Bristol knee score from 41.1 (sd 15.9) pre-operatively to 80.5 (sd 15) post-operatively (p < 0.001). At one year post-operatively both the total Bristol knee score and its functional component were significantly better in the restored group than in the elevated group (p < 0.01). Overall, revision from a unicondylar knee replacement required less use of bone graft, fewer component augments, restored the joint line more often and gave a significantly better total Bristol knee score (p < 0.02) and functional score (p < 0.01) than revision from total knee replacement.

Our findings show that restoration of the joint line at revision total knee replacement gives a significantly better result than leaving it unrestored by more than 5 mm. We recommend the greater use of distal femoral augments to help to achieve this goal.


The Bone & Joint Journal
Vol. 95-B, Issue 11 | Pages 1480 - 1483
1 Nov 2013
Hooper GJ Gilchrist N Maxwell R March R Heard A Frampton C

We studied the bone mineral density (BMD) and the bone mineral content (BMC) of the proximal tibia in patients with a well-functioning uncemented Oxford medial compartment arthroplasty using the Lunar iDXA bone densitometer. Our hypothesis was that there would be decreased BMD and BMC adjacent to the tibial base plate and increased BMD and BMC at the tip of the keel.

There were 79 consecutive patients (33 men, 46 women) with a mean age of 65 years (44 to 84) with a minimum two-year follow-up (mean 2.6 years (2.0 to 5.0)) after unilateral arthroplasty, who were scanned using a validated standard protocol where seven regions of interest (ROI) were examined and compared with the contralateral normal knee. All had well-functioning knees with a mean Oxford knee score of 43 (14 to 48) and mean Knee Society function score of 90 (20 to 100), showing a correlation with the increasing scores and higher BMC and BMD values in ROI 2 in the non-implanted knee relative to the implanted knee (p = 0.013 and p = 0.015, respectively).

The absolute and percentage changes in BMD and BMC were decreased in all ROIs in the implanted knee compared with the non-implanted knee, but this did not reach statistical significance. Bone loss was markedly less than reported losses with total knee replacement.

There was no significant association with side, although there was a tendency for the BMC to decrease with age in men. The BMC was less in the implanted side relative to the non-implanted side in men compared with women in ROI 2 (p = 0.027), ROI 3 (p = 0.049) and ROI 4 (p = 0.029).

The uncemented Oxford medial compartment arthroplasty appears to allow relative preservation of the BMC and BMD of the proximal tibia, suggesting that the implant acts more physiologically than total knee replacement. Peri-prosthetic bone loss is an important factor in assessing long-term implant stability and survival, and the results of this study are encouraging for the long-term outcome of this arthroplasty.

Cite this article: Bone Joint J 2013;95-B:1480–3.


The Bone & Joint Journal
Vol. 95-B, Issue 10 | Pages 1354 - 1358
1 Oct 2013
Singh G Tan JH Sng BY Awiszus F Lohmann CH Nathan SS

The optimal management of the tibial slope in achieving a high flexion angle in posterior-stabilised (PS) total knee replacement (TKR) is not well understood, and most studies evaluating the posterior tibial slope have been conducted on cruciate-retaining TKRs. We analysed pre- and post-operative tibial slope differences, pre- and post-operative coronal knee alignment and post-operative maximum flexion angle in 167 patients undergoing 209 TKRs. The mean pre-operative posterior tibial slope was 8.6° (1.3° to 17°) and post-operatively it was 8.0° (0.1° to 16.7°). Multiple linear regression analysis showed that the absolute difference between pre- and post-operative tibial slope (p < 0.001), post-operative coronal alignment (p = 0.02) and pre-operative range of movement (p < 0.001) predicted post-operative flexion. The variance of change in tibial slope became larger as the post-operative maximum flexion angle decreased. The odds ratio of having a post-operative flexion angle < 100° was 17.6 if the slope change was > 2°. Our data suggest that recreation of the anatomical tibial slope appears to improve maximum flexion after posterior-stabilised TKR, provided coronal alignment has been restored.

Cite this article: Bone Joint J 2013;95-B:1354–8.


The Bone & Joint Journal
Vol. 95-B, Issue 11_Supple_A | Pages 135 - 139
1 Nov 2013
Reinhardt KR Osoria H Nam D Alexiades MA Figgie MP Su EP

Blood loss during total knee replacement (TKR) remains a significant concern. In this study, 114 patients underwent TKR, and were divided into two groups based on whether they received a new generation fibrin sealant intra-operatively, or a local infiltration containing adrenaline. Groups were then compared for mean calculated total blood volume (TBV) loss, transfusion rates, and knee range of movement. Mean TBV loss was similar between groups: fibrin sealant mean was 705 ml (281 to 1744), local adrenaline mean was 712 ml (261 to 2308) (p = 0.929). Overall, significantly fewer units of blood were transfused in the fibrin sealant group (seven units) compared with the local adrenaline group (15 units) (p = 0.0479). Per patient transfused, significantly fewer units of blood were transfused in the fibrin sealant group (1.0 units) compared with the local adrenaline group (1.67 units) (p = 0.027), suggesting that the fibrin sealant may reduce the need for multiple unit transfusions. Knee range of movement was similar between groups. From our results, it appears that application of this newer fibrin sealant results in blood loss and transfusion rates that are low and similar to previously applied fibrin sealants.

Cite this article: Bone Joint J 2013;95-B, Supple A:135–9.


Bone & Joint Research
Vol. 3, Issue 1 | Pages 14 - 19
1 Jan 2014
James SJ Mirza SB Culliford DJ Taylor PA Carr AJ Arden NK

Aims

Osteoporosis and abnormal bone metabolism may prove to be significant factors influencing the outcome of arthroplasty surgery, predisposing to complications of aseptic loosening and peri-prosthetic fracture. We aimed to investigate baseline bone mineral density (BMD) and bone turnover in patients about to undergo arthroplasty of the hip and knee.

Methods

We prospectively measured bone mineral density of the hip and lumbar spine using dual-energy X-ray absorptiometry (DEXA) scans in a cohort of 194 patients awaiting hip or knee arthroplasty. We also assessed bone turnover using urinary deoxypyridinoline (DPD), a type I collagen crosslink, normalised to creatinine.