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Dr. Marc Wein: Extra attention should be paid to fracture risk in COPD patients receiving high-dose inhaled corticosteroids

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Marc Wein, M.D., Ph.D

Although the effects of vitamin K on blood coagulation are well-established, it is now clear that many extracellular proteins are carboxylated in a vitamin K-dependent manner, including bone matrix proteins such as osteocalcin and matrix gla protein. Previous studies have reported a relationship between vitamin K levels and bone density and fracture risk. However, optimal circulating vitamin K levels for skeletal health remain unknown. In this cross-sectional study of 374 women with post-menopausal osteoporosis, the authors assessed the relationship between vitamin K levels, vitamin K dependent bone-relevant circulating proteins, bone density, and fractures. In doing so, it was noted that women with prevalent fractures showed lower vitamin K levels than those without fractures. No relationship between vitamin K levels and bone density was noted. Interestingly, different serum levels of vitamin K were associated with optimal carboxylation of different vitamin K-dependent proteins: lower vitamin K levels are needed to support clotting factors than bone matrix proteins. Overall, this study suggests that higher intake is needed to obtain the full skeletal benefit of vitamin K versus its effects on coagulation. Future prospective studies are needed to test this intriguing hypothesis, and to further explore the relationship between vitamin K and bone quality.

For over 20 years, bisphosphonates have been first line therapy to increase bone density and reduce fracture risk in patients with osteoporosis. At present, multiple oral and intravenous bisphosphonates are approved for this indication by regulatory agencies worldwide. Several ‘next-generation’ bisphosphonates with optimized anti-resorptive and pharmacokinetic properties have been developed. Of these agents, minodronate is a particularly potent, third generation azaryl bisphosphonate that is currently approved for osteoporosis treatment in Japan. In this meta-analysis of 13 randomized controlled trials, the effects of minodronate were assessed versus other commonly-used osteoporosis medications. Compared with other drugs (alendronate, risedronate, raloxifene, or eldecalcitol), minodronate more potently suppressed serum bone resorption markers (NTX and TRAcP-5b) and, because bone formation and resorption are coupled, more potently suppressed the bone formation marker bone-specific alkaline phosphatase. In addition to these effects on serum markers, minodronate reduced vertebral fractures more than other medications. Across studies, no differences were noted between minodronate and comparators at the level of bone mineral density. Minodronate treatment is associated with a high incidence of gastrointestinal adverse effects than comparator medications. Taken together, these findings suggest that minodronate represents a potent, orally-available bisphosphonate for vertebral fracture reduction in patients with osteoporosis in Japan.

Chronic obstructive pulmonary disease (COPD) is well-known to be a risk factor for osteoporosis and fragility fractures. However, the interplay between inhaled corticosteroid use in COPD and skeletal outcomes remains unclear. While systemic glucocorticoid therapy clearly impairs bone mass and increases fracture risk, whether inhaled steroids have similar effects remain unknown. Furthermore, since inhaled corticosteroids can reduce lung inflammation and COPD flares, it is possible that, by controlling pulmonary disease, these agents may actually promote bone health. In this real-world retrospective Swedish cohort study, 9,651 COPD patients and 59,454 reference controls were identified. Matching using propensity scoring was performed to identify two populations (COPD and control) with similar characteristics other than the presence of COPD. As expected, COPD patients showed an increased rate of osteoporosis-related events versus controls over approximately 5 years of subsequent follow-up. Amongst COPD patients, high-dose inhaled corticosteroid treatment also increased risk of osteoporosis-related events compared to COPD patients on no or low-dose inhaled steroids. These findings confirm the known relationship between COPD and fracture risk, and suggest that extra attention should be paid to fracture risk in COPD patients receiving high-dose inhaled corticosteroids.

Wrist fractures are common in patients with osteoporosis. In addition to causing pain and triggering functional decline, the presence of a wrist fracture indicates an increased risk of additional fragility fractures in the near future. Most wrist fractures occur in the ultradistal radius, a skeletal site rich in trabecular bone. In contrast, wrist bone density by DXA is most commonly reported in the distal 1/3 radius, a region of the radius with more cortical bone. Abaloparatide is a PTHrP analog that increases bone density and reduces fracture risk. In this sub-analysis of the ACTIVE and ACTIVExtend randomized clinical trial, the effects of abaloparatide on wrist fractures and BMD at various regions of the wrist were assessed. Compared to placebo, abaloparatide treatment significantly increased ultradistal wrist BMD after 18 months of therapy. These gains were preserved during the subsequent extension study when patients were maintained on alendronate. Very few wrist fractures were noted during this study thus precluding robust statistical analysis of the effects of abaloparatide on wrist fracture risk. However, numerically fewer wrist fractures were noted in abaloparatide-treated patients versus controls. Taken together, these results highlight the potential importance of measuring ultradistal radius BMD for patients undergoing therapy with bone anabolic agents. Future studies are needed to better standardize methods for obtaining ultradistal radius BMD measurements and to define least significant change thresholds at this potentially-important skeletal site.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

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