Can bone turnover markers help to define the suitability and duration of bisphosphonate drug holidays?

BACKGROUND: On stopping bisphosphonate treatment, bone resorption may increase before evidence of a decrease in bone density. Offset of bisphosphonate effect may therefore be monitored by measuring C-terminal telopeptide (CTX) following long-term bisphosphonate treatment to inform clinical decisions on drug holiday. METHODS: Retrospective analysis of 158 patients (83% female, mean age 71 years) starting a drug holiday had plasma CTX measured at discontinuation (baseline), n=138 and 4 months and n=136, and 12 months (n=100). Premenopausal mean CTX levels and the least significant change (LSC) detectable were used to define target thresholds for bone turnover. RESULTS: Following long-term bisphosphonate treatment (69% alendronic acid, 33% risedronate, mean duration 8 years SD 2.7), 32% patients had CTX above target (0.19 µg/L). In those with baseline CTX below threshold, 28% increased CTX to >0.19 µg/L and > LSC (0.06 µg/L) by 4 months (mean CTX increase 0.05 µg/L [95% confidence interval (CI): 0.04-0.06; p<0.0001]) and 53% by 12 months (mean CTX increase 0.09 µg/L [95% CI: 0.07-0.10; p<0.0001]), whilst 47% had no detectable changes in CTX over 12 months. CONCLUSION: A third of patients showed inadequate suppression of CTX at baseline, despite long-term bisphosphonate treatment. Drug holiday may not be appropriate for this group, showing a poor therapeutic response or poor adherence. For more than a quarter of patients, bisphosphonate effects were wearing off at 4 months and around half by 12 months. We suggest CTX monitoring could identify those not experiencing a sustained bisphosphonate effect, including poorly adherence to therapy, and may be used during a drug holiday to prompt recommencement of therapy.

A Vitamin D, Calcium and Leucine-Enriched Whey Protein Nutritional Supplement Improves Measures of Bone Health in Sarcopenic Non-Malnourished Older Adults: The PROVIDE Study.

Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm2; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.

Osteoporosis and the Ageing Skeleton.

Osteoporosis is a "skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture" which, in light of demographic change, is becoming an increasing burden on health care worldwide. Increasing age and female gender are associated with the condition, although a wider range of clinical risk factors are being used increasingly to identify those at risk of osteoporosis and its most important sequelae, fracture.While osteoporosis and fracture have long been associated with women in the post-menopausal age, fracture incidence increases because of the ageing of our population. Interventions to abate the progression of osteoporosis and to prevent fractures must focus on the old and the very old. Evidence associating nutritional factors, particularly calcium and vitamin D are reviewed as are the association of falls risk with fracture and the potential for interventions to prevent falls. Finally, the assessment of frailty in the oldest old, associated sarcopenia and multi-morbidity are considered in the evaluation of fall and fracture risk and the management of osteoporosis in the ninth decade of life and beyond.

Randomized controlled trial of vitamin D supplementation in older people to optimize bone health.

Background: Vitamin D insufficiency is common in older people and may lead to increased bone resorption, bone loss, and increased falls and fractures. However, clinical trials assessing the effect of vitamin D supplementation on bone mineral density (BMD) have yielded conflicting results. Objectives: This study examined the effect of vitamin D supplementation on BMD at the hip, using dual-energy X-ray absorptiometry. Methods: A total of 379 adults aged ≥70 y (48% women; mean age: 75 y) from the northeast of England were randomly allocated to 1 of 3 doses of vitamin D3 [12,000 international units (IU), 24,000 IU, or 48,000 IU] given once a month. The primary outcome was change in BMD (ΔBMD) at the hip. Secondary endpoints comprised the dose effects on femoral neck BMD, falls, circulating calciotropic hormones, bone turnover markers, and adverse events. Results: The mean ± SD baseline plasma 25-hydroxyvitamin D [25(OH)D] concentration was 40.0 ± 20.1 nmol/L, which increased after 12 mo to a mean 25(OH)D of 55.9, 64.6, or 79.0 nmol/L for participants receiving a monthly dose of 12,000, 24,000, or 48,000 IU, respectively (P < 0.01 for difference). There was no between-group difference in ΔBMD. However, parathyroid hormone concentrations decreased in all 3 groups, with a significantly greater decrease in the 48,000-IU group compared with the 12,000-IU group (P < 0.01). There were no differences in any adverse events between groups, with 3 cases of hypercalcemia, none of nephrolithiasis, and 249 falls observed. Conclusions: There was no difference in change in BMD over 12 mo between the 3 doses of vitamin D, suggesting no effect of the intervention or a similar attenuation of the anticipated decrease in BMD over 12 mo. The treatment was safe and effective in increasing plasma 25(OH)D concentrations, with no dose-related adverse events. This trial was registered at the EU Clinical Trials Register (EudraCT 2011-004890-10) and the ISRCTN Registry (ISRCTN35648481).

Implications of guidelines for osteoporosis and its treatment.

The development of clinical guidelines is now a more uniform process, with formalised methods to ensure that recommendations are based on current best available evidence from randomised controlled trials and systematic reviews. Over the past 20 years we have seen a growth in guidelines including those relating to osteoporosis, with recommendations varying between and within countries. Some guidelines are concerned with case finding and primary or secondary prevention, such as those produced by the National Institute for Health and Care Excellence (NICE CG146, TA-160, -161, -464), while others focus on specific conditions or risk factors associated with osteoporosis, such as the menopause, coeliac disease and eating disorder. Clinicians can be confused as to which to follow in any particular clinical scenario. International guidelines, such as those from North America (NOF, CAROC, AACE) and Scotland (SIGN 142), differ from those of England, Wales and Northern Ireland, with recent recommendations from NICE (TA464) shifting the focus of treatment from those at greatest fracture risk to an apparent blanket approach, based on cost-effectiveness, rather than clinical effectiveness.Osteoporosis treatment should be targeted at those who can benefit most, outweighing the potential for harm. If the low health economic threshold of NICE TA464 were adopted as a clinical threshold, the most important group-older people at greatest risk of fracture, would not be prioritised. We risk overwhelming clinical services, while causing harm to some at low fracture risk from adverse effects of treatment, yet failing to treat the older population at highest fracture risk.

The role of vitamin D in maintaining bone health in older people.

This review summarises aspects of vitamin D metabolism, the consequences of vitamin D deficiency, and the impact of vitamin D supplementation on musculoskeletal health in older age. With age, changes in vitamin D exposure, cutaneous vitamin D synthesis and behavioural factors (including physical activity, diet and sun exposure) are compounded by changes in calcium and vitamin D pathophysiology with altered calcium absorption, decreased 25-OH vitamin D [25(OH)D] hydroxylation, lower renal fractional calcium reabsorption and a rise in parathyroid hormone. Hypovitaminosis D is common and associated with a risk of osteomalacia, particularly in older adults, where rates of vitamin D deficiency range from 10-66%, depending on the threshold of circulating 25(OH)D used, population studied and season. The relationship between vitamin D status and osteoporosis is less clear. While circulating 25(OH)D has a linear relationship with bone mineral density (BMD) in some epidemiological studies, this is not consistent across all racial groups. The results of randomized controlled trials of vitamin D supplementation on BMD are also inconsistent, and some studies may be less relevant to the older population, as, for example, half of participants in the most robust meta-analysis were aged under 60 years. The impact on BMD of treating vitamin D deficiency (and osteomalacia) is also rarely considered in such intervention studies. When considering osteoporosis, fracture risk is our main concern, but vitamin D therapy has no consistent fracture-prevention effect, except in studies where calcium is coprescribed (particularly in frail populations living in care homes). As a J-shaped effect on falls and fracture risk is becoming evident with vitamin D interventions, we should target those at greatest risk who may benefit from vitamin D supplementation to decrease falls and fractures, although the optimum dose is still unclear.

The effects of parathyroid hormone peptides on the peripheral skeleton of postmenopausal women. A systematic review.

Given current developments in anabolic therapy for bone, we wished to document the effects of the only currently available anabolic therapy, parathyroid hormone (PTH) peptides, on the peripheral skeleton of postmenopausal women. We undertook a systematic review of English articles using MEDLINE, Scopus and the Cochrane Controlled Trials Register (final update 28th March 2016). Additional studies were identified through searches of bibliographies. Studies included those comparing PTH peptides with placebo, with anti-osteoporotic treatments and in combination therapies. Participants had to be postmenopausal women and outcomes included areal or volumetric bone mineral density (BMD) and measurements of bone microarchitecture at peripheral sites, such as the forearm and tibia. Data were extracted independently and reviewed by EVM and LMM. Data on study design were also collected for methodological risk of bias assessment. The heterogeneity between studies, regarding the drug dose and duration, and the site measured, prevented grouped meta-analysis. There were no significant differences in areal BMD between PTH peptides and placebo at peripheral skeletal sites at 12months. A decrease in aBMD occurred with PTH(1-34) (larger dose) and PTH(1-84) treatment at 18months follow-up in comparison to the placebo arms. Anti-resorptives seemed to attenuate losses of aBMD at peripheral sites when compared to PTH peptides monotherapy, likely mediated by lower cortical porosity. Finally, PTH peptides combined with bisphosphonates or denosumab attenuated peripheral BMD losses in comparison to PTH peptide monotherapy, with evidence of increased BMD at ultradistal peripheral sites when PTH(1-34) was combined with denosumab or hormone replacement therapy. This summary should act as a reference point for the comparison of new anabolic therapies, specifically in comparison to PTH(1-34).

Nutritional status, body composition, and quality of life in community-dwelling sarcopenic and non-sarcopenic older adults: A case-control study.

BACKGROUND & AIM: Sarcopenia, the age-related decrease in muscle mass, strength, and function, is a main cause of reduced mobility, increased falls, fractures and nursing home admissions. Cross-sectional and prospective studies indicate that sarcopenia may be influenced in part by reversible factors like nutritional intake. The aim of this study was to compare functional and nutritional status, body composition, and quality of life of older adults between age and sex-matched older adults with and without sarcopenia. METHODS: In a multi-centre setting, non-sarcopenic older adults (n = 66, mean ± SD: 71 ± 4 y), i.e. Short Physical Performance Battery (SPPB): 11-12 and normal skeletal muscle mass index, were recruited to match 1:1 by age and sex to previously recruited adults with sarcopenia: SPPB 4-9 and low skeletal muscle mass index. Health-related quality of life, self-reported physical activity levels and dietary intakes were measured using the EQ-5D scale and index, Physical Activity Scale for the Elderly (PASE), and 3-day prospective diet records, respectively. Concentrations of 25-OH-vitamin D, α-tocopherol (adjusted for cholesterol), folate, and vitamin B-12 were assessed in serum samples. RESULTS: In addition to the defined components of sarcopenia, i.e. muscle mass, strength and function, reported physical activity levels and health-related quality of life were lower in the sarcopenic adults (p < 0.001). For similar energy intakes (mean ± SD: sarcopenic, 1710 ± 418; non-sarcopenic, 1745 ± 513, p = 0.50), the sarcopenic group consumed less protein/kg (-6%), vitamin D (-38%), vitamin B-12 (-22%), magnesium (-6%), phosphorus (-5%), and selenium (-2%) (all p < 0.05) compared to the non-sarcopenic controls. The serum concentration of vitamin B-12 was 15% lower in the sarcopenic group (p = 0.015), and all other nutrient concentrations were similar between groups. CONCLUSIONS: In non-malnourished older adults with and without sarcopenia, we observed that sarcopenia substantially impacted self-reported quality of life and physical activity levels. Differences in nutrient concentrations and dietary intakes were identified, which might be related to the differences in muscle mass, strength and function between the two groups. This study provides information to help strengthen the characterization of this geriatric syndrome sarcopenia and indicates potential target areas for nutritional interventions.

Fragility fracture: recent developments in risk assessment.

More than half of older women who sustain a fragility fracture do not have osteoporosis by World Health Organization (WHO) bone mineral density (BMD) criteria; and, while BMD has been used to assess fracture risk for over 30 years, a range of other skeletal and nonskeletal clinical risk factors (CRFs) for fracture have been recognized. More than 30 assessment tools using CRFs have been developed, some predicting fracture risk and others low BMD alone. Recent systematic reviews have reported that many tools have not been validated against fracture incidence, and that the complexity of tools and the number of CRFs included do not ensure best performance with poor assessment of (internal or comparative) validity. Internationally, FRAX® is the most commonly recommended tool, in addition to QFracture in the UK, The Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool in Canada and Garvan in Australia. All tools estimate standard 10-year risk of major osteoporotic and 10-year risk of hip fracture: FRAX® is able to estimate fracture risk either with or without BMD, but CAROC and Garvan both require BMD and QFracture does not. The best evidence for the utility of these tools is in case finding but there may be future prospects for the use of 10-year fracture risk as a common currency with reference to the benefits of treatment, whether pharmacological or lifestyle. The use of this metric is important in supporting health economic analyses. However, further calibration studies will be needed to prove that the tools are robust and that their estimates can be used in supporting treatment decisions, independent of BMD.

National Osteoporosis Society vitamin D guideline summary.

The National Osteoporosis Society (NOS) published its document, Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management, in 2013 as a practical clinical guideline on the management of vitamin D deficiency in adult patients with, or at risk of developing, bone disease. There has been no clear consensus in the UK on vitamin D deficiency its assessment and treatment, and clinical practice is inconsistent. This guideline is aimed at clinicians, including doctors, nurses and dieticians. It recommends the measurement of serum 25 (OH) vitamin D (25OHD) to estimate vitamin D status in the following clinical scenarios: bone diseases that may be improved with vitamin D treatment; bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate; musculoskeletal symptoms that could be attributed to vitamin D deficiency. The guideline also states that routine vitamin D testing is unnecessary where vitamin D supplementation with an oral antiresorptive treatment is already planned and sets the following serum 25OHD thresholds: <30 nmol/l is deficient; 30-50 nmol/l may be inadequate in some people; >50 nmol/l is sufficient for almost the whole population. For treatment, oral vitamin D3 is recommended with fixed loading doses of oral vitamin D3 followed by regular maintenance therapy when rapid correction of vitamin D deficiency is required, although loading doses are not necessary where correction of deficiency is less urgent or when co-prescribing with an oral antiresorptive agent. For monitoring, serum calcium (adjusted for albumin) should be checked 1 month after completing a loading regimen, or after starting vitamin D supplementation, in case primary hyperparathyroidism has been unmasked. However, routine monitoring of serum 25OHD is generally unnecessary but may be appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where poor compliance with medication is suspected. The guideline focuses on bone health as, although there are numerous putative effects of vitamin D on immunity modulation, cancer prevention and the risks of cardiovascular disease and multiple sclerosis, there remains considerable debate about the evaluation of extraskeletal factors and optimal vitamin D status in these circumstances.

New horizons in fracture risk assessment.

Fracture is the clinical outcome of concern in osteoporosis, a disease variably defined over the last 30 years, mostly in terms of bone mineral density (BMD). However, an 'osseocentric' view of the condition may have hampered our understanding of how best to identify patients at the greatest risk of fragility fracture. More recently, the identification of a number of clinical risk factors for fragility fracture and the creation of fracture risk assessment tools, such as FRAX®, QFracture and Garvan have helped in a move towards clinically useful definitions, using the common currency of 10-year major osteoporotic and 10-year hip fracture risks. However, there are a large number of available fracture risk assessment tools and there remain few validation studies comparing their performance. The National Institute for Health and Clinical Excellence has recently advocated the use of these methods in case finding and studies are underway in their clinical application. It seems likely that the operational definition of osteoporosis must now include fracture risk, which will never replace fracture incidence as a measure of clinical efficacy but may be used in future studies to define patient groups likely to benefit from intervention. We still need to understand more about the performance of these tools, particularly in the context of specific patient groups, such as those with vertebral osteoporosis, the frail, those who fall and patients with secondary osteoporosis.

Treatment of osteoporosis in women intolerant of oral bisphosphonates.

In the past 15 years, oral bisphosphonate therapy has become the mainstay of pharmacological management in patients with osteoporosis. In the UK, alendronate is the drug of first choice, based on clinical efficacy data and cost. However, some patients are unable to take oral bisphosphonates for a number of reasons. In this article, we review the practical management of such cases, including strategies for monitoring adherence and switching to alternative oral agents (e.g. risedronate, strontium ranelate, raloxifene). In some cases, alternative parenteral agents may be considered, including intravenous bisphosphonates, parathyroid hormone therapies and denosumab. Specific concerns about safe prescribing are considered, when prescribing potent anti-resorptive medications, particularly relating to renal function and vitamin D deficiency. Finally, consideration is given to clinical risk factors, including aspects of lifestyle which may be modified to decrease fracture risk.