Bone turnover change after randomized switch from tenofovir disoproxil to tenofovir alafenamide fumarate in men with HIV.

OBJECTIVE: Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate. DESIGN: Open-label, randomized controlled trial. SETTING: Single-site, outpatient, secondary care. PARTICIPANTS: Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks. INTERVENTION: Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization). MAIN OUTCOME MEASURES: :[ 18 F]NaF-PET/CT for bone turnover (standardized uptake values, SUV mean ) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD. RESULTS: Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23-103 (median 55) weeks. LS-SUV mean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P  = 0.57). TH-SUV mean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P  = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P  = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX ( P  = 0.02, P1NP, P  = 0.17). CONCLUSION: Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUV mean ) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUV mean may be due to inadequate power.

The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial.

This study assessed whether vitamin K, given with oral bisphosphonate, calcium and/or vitamin D has an additive effect on fracture risk in post-menopausal women with osteoporosis. No difference in bone density or bone turnover was observed although vitamin K1 supplementation led to a modest effect on parameters of hip geometry. PURPOSE: Some clinical studies have suggested that vitamin K prevents bone loss and may improve fracture risk. The aim was to assess whether vitamin K supplementation has an additive effect on bone mineral density (BMD), hip geometry and bone turnover markers (BTMs) in post-menopausal women with osteoporosis (PMO) and sub-optimum vitamin K status receiving bisphosphonate, calcium and/or vitamin D treatment. METHODS: We conducted a trial in 105 women aged 68.7[12.3] years with PMO and serum vitamin K1 ≤ 0.4 µg/L. They were randomised to 3 treatment arms; vitamin K1 (1 mg/day) arm, vitamin K2 arm (MK-4; 45 mg/day) or placebo for 18 months. They were on oral bisphosphonate and calcium and/or vitamin D. We measured BMD by DXA, hip geometry parameters using hip structural analysis (HSA) software and BTMs. Vitamin K1 or MK-4 supplementation was each compared to placebo. Intention to treat (ITT) and per protocol (PP) analyses were performed. RESULTS: Changes in BMD at the total hip, femoral neck and lumbar spine and BTMs; CTX and P1NP did not differ significantly following either K1 or MK-4 supplementation compared to placebo. Following PP analysis and correction for covariates, there were significant differences in some of the HSA parameters at the intertrochanter (IT) and femoral shaft (FS): IT endocortical diameter (ED) (% change placebo:1.5 [4.1], K1 arm: -1.02 [5.07], p = 0.04), FS subperiosteal/outer diameter (OD) (placebo: 1.78 [5.3], K1 arm: 0.46 [2.23] p = 0.04), FS cross sectional area (CSA) (placebo:1.47 [4.09],K1 arm: -1.02[5.07], p = 0.03). CONCLUSION: The addition of vitamin K1 to oral bisphosphonate with calcium and/or vitamin D treatment in PMO has a modest effect on parameters of hip geometry. Further confirmatory studies are needed. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov:NCT01232647.

Serum vitamin K1 (phylloquinone) is associated with fracture risk and hip strength in post-menopausal osteoporosis: A cross-sectional study.

PURPOSE: Vitamin K may play a potential role in bone metabolism, although further evidence is needed. The mechanisms behind its skeletal effects and optimum intake for maintaining bone health remain poorly defined. To elucidate these two issues, we investigated the association between circulating vitamin K1 (phylloquinone) concentrations with fracture risk, bone mineral density (BMD), hip geometry and plasma dephospho-uncarboxylated-Matrix Gla Protein (dp-ucMGP), an extra-hepatic vitamin K dependent protein (VKDP), in post-menopausal osteoporosis (PMO). METHODS: We studied 374 women aged (mean [SD]) 68.7[12.3] years with PMO. Information including demographics, lifestyle habits and previous fractures was captured through a questionnaire. Serum was analysed for vitamin K1. BMD at the lumbar spine (LS), total hip (TH) and femoral neck (FN) (n = 277) and hip structural analysis (HSA) parameters (n = 263) were derived from DXA scans. VKDPs including undercarboxylated prothrombin (PIVKA-II) and dp-ucMGP were measured in a sub-group (n = 130). RESULTS: Serum vitamin K1 was significantly lower in the group with fractures (prevalent fractures: 0.53 [0.41], no fractures; 0.65 [0.66] µg/L, p = 0.04) and independently associated with fracture risk. The adjusted odds ratio (95% CI) per µg/L increase in vitamin K1 was 0.550 (0.310-0.978, p = 0.042). Among the HSA parameters, serum vitamin K1 was positively associated with cross-sectional area (CSA) (p = 0.02), cross sectional moment of inertia (CSMI) (p = 0.028) and section modulus (Z) (p = 0.02) at the narrow neck (NN) of femur. Dp-ucMGP was detectable in 97 (75%) participants with serum vitamin K1 of 0.26 [0.15] µg/L, whilst PIVKA-II was above the clinical threshold in only 3.8%. CONCLUSIONS: Our data suggest that the positive effect of vitamin K on fracture risk may be related to its effects on bone strength. Higher concentrations of serum vitamin K1 may be required for vitamin K's skeletal effects compared to coagulation. Further prospective or interventional studies are needed for confirmation and should include measures of bone quality.