Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli

Abstract

Long-term warfarin use has been reported to increase fracture risk of rib and vertebra but not hip in elderly patients, but the mechanisms remain unknown. We hypothesized that warfarin would impair bone material quality but could not weaken bone strength under conditions with higher mechanical stimuli. To test this hypothesis, rats were randomized to vehicle or warfarin group at 4 weeks of age and subsequently weight matched into a sedentary or jumping exercise group at 12 weeks of age. At 6 months of age, osteocalcin content, bone mineral density (BMD), mineral size, material properties, morphological parameters, and biomechanical properties of cortical bones were evaluated. In order to seek evidence for a common mechanism of action, effects of nucleation rate of mineral crystals on their rigidity were also investigated using computer simulation. In humeral cortical bones, warfarin did not change BMD, but markedly decreased osteocalcin content, diminished mineral size, and impaired material hardness. Consistent with these results, our computer-simulation model showed that osteocalcin-induced delay of mineral crystal nucleation decreased mineral formation rate, increased mean and distribution of mineral sizes, and strengthened mineral rigidity. In tibial cortical bones, warfarin decreased material ultimate stress; however, under jumping exercise, warfarin increased cross-sectional total and bone areas of these tibiae and completely maintained their biomechanical properties including work to failure. Collectively, our findings suggest that longterm warfarin therapy weakens rib and vertebra by impairing cortical bone material quality due to a marked decrease in osteocalcin content but could not reduce hip strength through compensatory adaptation of cortical bone structure to higher mechanical stimuli.

Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function

“…Our approach was different, as we reproduced the usual clinical setting, which is adapting warfarin dosage to keep the prothrombin INR in the 2 to 3 range. Furthermore, while high warfarin doses may block peripheral vitamin K activity, thereby inhibiting the γ-carboxylation of vascular MGP and of bone osteocalcin, the endogenous conversion of vitamin K1 to menaquinone-4 may contribute to the direct, osteocalcin-independent protective effects on bone [ 25 , 26 ].…”

“…Previous studies have established that vitamin K deficiency significantly affects bone health [ 26 , 32 – 36 ]. While there is some controversy as to whether warfarin decreases bone mineral density [ 33 ], there is agreement on warfarin-induced risk of rib and vertebral fractures in elderly patients [ 34 – 36 ], possibly by increasing skeletal fragility through the onset of vitamin K deficiency.…”

Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

“…c-carboxylation is also required for the development of other tissues, and warfarin exposure in utero can cause mental retardation, nasal, limb, or digit abnormalities in the fetus [24]. Warfarin may also interfere with the function of osteocalcin [25] and long-term warfarin use may be associated with osteoporotic fractures, at least in elderly men [26].…”

A Systematic Review and Meta-analysis of the Association Between Vitamin K Antagonist Use and Fracture

“…VKA use decreases bone osteocalcin levels, which decreases bone hardness. [2][3][4] Increased blood levels of undercarboxylated osteocalcin are associated with decreased bone mineral quality, 5 but an association between VKA use and decreased bone mineral density has not been found, 6,7 suggesting that agents can affect bone structure without affecting bone density.…”